Substituted 1,2,3-thiadiazole-4-thiolates

ABSTRACT

Intermediates useful for synthesis of cephalosporins are disclosed, which intermediates are concerned with 1,2,3-thiadiazole-4-thiolates and the preparation of such thiolates.

This is a divisional of application Ser. No. 06/883,189 filed July 8,1986.

SUMMARY OF THE INVENTION

This invention is concerned with1,2,3-thiadiazole-4-thiolateiintermediates which are useful in thepreparation of cephalosporanic acid derivatives having antibacterialactivity. Further, this invention is concerned with certainintermediates used to prepare such 1,2,3-thiadiazole-4-thiolates as wellas processes for their preparation.

In sequence, N² -thioacylcarbazates, N²-thioacylarenesulfonylhydrazides, and N³ -thioacylsemicarbazides of theformula: ##STR1## where R₁ is selected from the group consisting ofhydrogen; alkyl(C₁ -C₆); polyfluorinated alkyls(C₁ -C₆); phenyl;(multisubstituted)phenyl wherein the substituents are selected fromalkyl(C₁ -C₆), alkoxy(C₁ -C₃), chloro, fluoro and trifluoromethyl;naphthyl; thienyl; phenylthio; tetrahydropyranyl; benzyl; and --COOC₂ H₅; and R₂ is selected from the group consisting of amino and alkoxy(C₁-C₃), are used to produce N-acylthiohydrazonate esters (E and Z isomers)of the formula: ##STR2## where R₁ and R₂ are as described above and R₃is --CH₂ CH₂ COOR₄, where R₄ is alkyl(C₁ -C₃).

These N-acylthiohydrazonate esters are used to make either alkyl3-(1,2,3-thiadiazol-4-ylthio)propionates of the formula: ##STR3## whereR₁ is as described above and R₄ is alkyl(Cl-C3) or 4-(substitutedthio)-1,2,3-thiadiazoles of the formula: ##STR4## where R₁ is asdescribed above and R₅ is selected from the group consisting of alkyl(C₁-C₃); phenyl; alkenyl(C₃ -C₆); --CH₂ COOC₂ H₅ ; --C(CH₃)₂ COOC₂ H₅ and--CH₂ CH₂ CN.

Either the alkyl 3-(1,2,3-thiadiazol-4-ylthio)propionates or the4-(substituted thio)-1,2,3-thiadiazoles are then used to produce the1,2,3-thiadiazole-4-thiolates, which are the end products of thisinvention and are represented by the formula: ##STR5## where R₁ is asdescribed above and M is sodium or potassium.

DESCRIPTION OF THE INVENTION

The compounds of this invention may be prepared according to thefollowing reaction schemes: ##STR6##

According to Scheme I a (2-substituted-1-thioxyalkyl)thioglycolic acid1, where R1 is hydrogen, phenyl or 4-tert-butylphenyl is reacted with analkyl hydrazine carboxylate 2, where R₂ is methoxy or ethoxy, in asolvent such as chloroform or dichloromethane, at reflux, giving the N₂-thioacylcarazates 3 which are purified by conventional chromatography.##STR7##

According to Scheme II, a substituted methyl ketone 4, where R₁ is4-t-butylphenyl, 4-methoxyphenyl, 3,4,5-trimethoxyphenyl, naphthyl,thienyl or 3-methoxyphenyl is heated with piperidine and sulfur givingthe piperidine derivatives 5 which is then reacted with bromoacetic acidin an organic solvent giving the piperidinium bromide derivative 6 whichis reacted with hydrogen sulfide in an alkanol, at 0°-35° C., giving theacetic acid derivative 7, or aqlkyl esters thereof, which is thenreacted with an alkyl hydrazine carboxylate 2, where R₂ is methoxy orethoxy in a solvent such as dichloromethane, at reflux giving the N²-thioacylcarbazates 3 which are purified by chromatography. ##STR8##

According to Scheme III an acetic acid derivative 8, where R₁ is4-chlorophenyl, 4-fluorophenyl, 3-(trifluoromethyl)phenyl, C₂ H₅ OOC--,phenylthio or 2-tetrahydropyranyl, is reacted with thionyl chloride in asolvent such as benzene at reflux giving the acyl chloride derivative 9which is then reacted with piperidine in pyridine and ether giving thepiperidine derivative 10 which is reacted with phosphorus pentasulfidein pyridine at reflux giving piperidine derivative 5 followed byreaction as described in Scheme II to produce 3. ##STR9##

According to Scheme IV, an acetic acid ester 7, where R₁ is alkyl(C₁-C₆) or benzyl is reacted with semicarbazide hydrochloride 11 andanhydrous sodium acetate in ethanol with heat giving the compounds 3where R₂ is NH₂. ##STR10##

According to Scheme V an N² -thioacylcarbazate ester 3, where R₁ isalkyl(C₁ -C₆), phenyl, benzyl, 3-methoxyphenyl, 4-methoxyphenyl,3,4,5-trimethoxyphenyl, 4-t-butylphenyl, naphthyl, thienyl,4-chlorophenyl, 4-fluorophenyl, 3-(trifluoromethyl)phenyl, phenylthio ortetrahydropyranyl and R₂ is alkoxy(C₁ -C₃) is reacted with an acrylate12 where R₄ is methyl or ethyl and triethylam in benzene, at refluxgiving a hydrazinecarboxylic acid ester 13 (E and Z isomers) which isthen reacted with thionyl chloride in benzene at reflux, giving the[(1,2,3-thiadiazol-4-yl)thio]propanoic acid esters 14. ##STR11##

According to Scheme VI a substituted thioacylsemicarbazide 3, where R₁is alkyl(C₁ -C₆) is reacted with potassium carbonate and an alkyl3-iodopropionate in acetone at reflux, giving a hydrazono propanoic acidderivative 15 (E and Z isomers), which is then reacted with thionylchloride in dichloromethane, giving the 1,2,3-thiadiazole derivatives14. ##STR12##

According to Scheme VII an acetyl chloride 9, where R₁ is hydrogen ort-butyl is reacted with an alkyl hydrazine carboxylate 2, where R₂ ismethyl or ethyl in pyridine and diclhloromethane at 0°-5° C., givinghydrazine derivative 16 which is reacted with phosphorus pentachloridein chloroform, followed by reaction with sodium thiophenoxide intetrahydrofuran, giving phenylthio derivative 17 which is then reactedwith thionyl chloride in chloroform at reflux giving4-(phenylthio)-12,3-thiadiazole 18.

Alternately, reaction of 16 with phosphorus pentachloride in chloroform,followed by reaction with sodium (or potassium) ethyl (ormethyl)-propionate-3-thiolate in tetrahydrofuran, giving derivative 13which is then reacted with thionyl chloride in methylene chloride atreflux giving 1,2,3-thiadiazoles 14. ##STR13##

According to Scheme VIII a methylthio hydrazine derivative 19, where R₁is thienyl or 4-methoxyphenyl and R₂ is methyl or ethyl is reacted withthionyl chloride giving the 4-(methylthio)-1,2,3-thiadiazole derivatives20, ##STR14##

According to Scheme IX a [(1,2,3-thiadiazol-4-yl)thio]propanoic acidester 14, where R₁ is as disclosed in this invention and R₄ is methyl orethyl is reacted with sodium or potassium alkoxide in an alkanol, givingthe products 21.

This invention will be described in detail in conjunction with thefollowing non-limiting examples.

EXAMPLE 1 2-(1-Thioxoethyl)hydrazinecarboxylic acid, methyl ester

A mixture of 129 g of 2-(1-thioxoethyl)thioglycolic acid, ethyl ester,67.5 g of methyl hydrazinocarboxylate and 500 ml of chloroform washeated at reflux for 8 hours, then concentrated in vacuo. The oilyresidue was concentrated further under high vacuum, giving a yellow oil.This oil was dissolved in 500 ml of dichloromethane and passed through abed of hydrous magnesium silicate, washing with additionaldichloromethane. The resulting light yellow oil was crystallized fromtoluene-methylcyclohexane, giving 70 g of the desired compound as ivorycrystals, mp 99-100.5° C. Proton nuclear magnetic resonance (δ [ppm],CDCl₃) 90MHz: 2.42 (s, 3H, CH₃ CS); 3.76 (s, 3H, OCH₃); 8.55 (bs, 1H,NH); 9.56 (bs, 1H, NH).

EXAMPLE 2 2-(1-Thioxoethyl)hydrazinecarboxylic acid, ethyl ester

A mixture of 110 g of 2-(1-thioxoethyl)thioglycolic acid, ethyl ester,65.2 g of ethyl hydrazinocarboxylate and 500 ml of dichloromethane washeated at reflux for 3 hours, then concentrated in vacuo. The oilyresidue was concentrated further under high vacuum, giving a yellow oil.This oil was dissolved in 500 ml of dichloromethane and passed through abed of hydrous magnesium silicate, washing with additionaldichloromethane. The resulting light yellow oil was crystallized fromdiisopropyl ether giving a 79% yield of the desired compound as ivorycrystals, mp 54.0-57.5° C. Proton nuclear magnetic resonance (δ ppm],CDCl₃) 90MHz: 1.30 (t, 3H, J =7.4Hz, CH₃ CH₂); 2.55 (s, 3H, CH₃ CS);4.25 (q, 2H, CH₂ CH₃); 8.75 (bs, 1H, NH); 10.35 (bs, NH).

EXAMPLE 3 2-(3,3-Dimethyl-1-thioxobutyl)hydrazinecarboxylic acid, methylester

A mixture of 122 g of 2-(3,3-dimethyl-1-thioxobutyl)thioglycolic acid,methyl ester, 54.3 g of methyl hydrazinocarboxylate and 750 ml ofdichloromethane was heated at reflux for one hour, then concentrated invacuo. The orange residue was taken up in ether, washed twice with waterand then three times with 0.5N sodium hydroxide. The alkaline extractswere combined, back washed with ether and then acidified with 2Nhydrochloric acid to pH 3. The product was extracted into ether andworked up to give a light orange viscous oil. This oil was taken up indichloromethane, applied to a 60mm×600mm, 60 g column of silica gel(200-400 mesh) packed in dichloromethane and eluted with a gradient of0-10% methanol in dichloromethane. The desired fractions were collected,giving 93.0 g of a light yellow oil. This oil was crystallized frommethylcyclohexane, giving 91.0 g (81% yield) of the desired compound asivory crystals, mp 72.5-73° C. Proton nuclear magnetic resonance (δ[ppm], CDCl₃) 90MHz: 1.07 (s, 9H, t-butyl); 2.63 (s, 2H, CH₃ CS); 3.80(s, 3H, OCH₃); 8.75 (bs, 1H, NH); 9.65 (bs, 1H, NH).

EXAMPLE 4 2-(2-Phenyl-1-thioxoethyl)hydrazinecarboxylic acid, methylester

A mixture of 86.0 g of 2-(2-phenyl-1-thioxoethyl)thioglycolic acid, 195ml of 2N sodium hydroxide and 100 ml of water was added dropwise to asuspension of 50 g of methyl hydrazinocarboxylate in 200 ml of waterwith vigorous stirring. Stirring was continued overnight, then themixture was extracted twice with ether. The extracts were combined,washed successively with 5% aqueous sodium bicarbonate (twice), waterand saturated aqueous sodium chloride, dried and concentrated in vacuo.The dark orange oil was purified by percolation through a bed of hydrousmagnesium silicate with dichloromethane. The resulting pale yellow oilwas chromatographed on a 70×850 mm dry column of silica gel, elutingwith dichloromethane. The resulting oil was crystallized fromtoluene-hexane, giving 42.6 g of the desired compound as yellowcrystals, mp 93.5-94° C. Proton nuclear magnetic resonance (δ[ppm],CDCl₃) 90MHz: 3.79 (s, 3H, OCH₃); 4.11 (s, 2H, CH₃ CS); 7.33 (bs, 5H, C₆H₅); 8.65 (bs, 1H, NH); 9.55 (bs, 1H, NH).

EXAMPLE 5 2-[2-(4-Methylphenyl)-1-thioxoethyl]hydrazinecarboxylic acid,methyl ester

A mixture of 37.0 g of 2-[2-(4-methylphenyl)-1thioxoethyl]thioglycolicacid, 18.2 g of methyl hydrazinocarboxylate and 250 ml ofdichloromethane was heated at reflux for one hour and then evaporated invacuo. The residue was concentrated at high vacuum and 45° C. for onehour. The oily residue was chromatographed on a 75×800 mm dry column ofsilica gel, eluting with dichloromethane. The desired fractions werepooled and the solid crystallized from toluene-hexane, giving 30 g ofthe desired compound as off-white needles, mp 104.5-105° C. Protonnuclear magnetic resonance (δ[ppm], CDCl₃) 90MHz: 2.38 (s, CH₃); 3.79(s, 3H, OCH₃); 4.07 (s, 2H, CH₂ CS); 7.23 (s, 4H, C₆ H₄); 8.68 (bs, 1H,NH); 9.52 (bs, 1H, NH).

EXAMPLE 6 2-[2-[4-(1,1-Dimethylethyl)phenyl]-1-thioxoethyl]-hydrazinecarboxylic acid, methyl ester

A mixture of 176.1 g of 4-(tert-butyl)acetophenone, 128 g of piperidineand 48.5 g of powdered sulfur was heated at reflux for 14 hours, thencooled and concentrated in vacuo. The residue was taken up in a mixtureof ether and water and then extracted twice with ether. The organicextracts were combined, washed successively with water, 5% hydrochloricacid, water and saturated aqueous sodium chloride, then dried andconcentrated. The resulting oil was diluted with 1.5 liters of hexaneand cooled at -60 to -75° C. for 3 hours. The resulting solid wascollected, washed with cyclohexane, then dissolved in dichloromethane,decolorized with charcoal and crystallized from cyclohexane, giving 138g of N-[2-(4-t-butylphenyl)-1-thioxoethyl]piperidine.

A mixture of 137.6 g of the above compound, 76.5 g of bromoacetic acidand 500 ml of benzene was stirred overnight and then diluted with 1.5liters of ether. The solid was collected, washed with ether and dried invacuo, giving1-[1-[(carboxymethyl)thio]-2-(4-t-butylphenyl)ethylidene]piperidiniumbromide.

A suspension of 124.2 g of the above compound in 500 ml of ethanol wastreated with gaseous hydrogen sulfide at 0° C. for 5 hours, then storedovernight at 0° C. The solvent was removed in vacuo and the semi-solidsuspended in 700 ml of dry ether, then filtered. The filter cake waswashed with ether to remove all coloration. The combined filtrate andwashings were extracted three times with 0.1N sodium hydroxide. Thecombined alkaline extract was acidified and then extracted twice withether. The organic extracts were combined, washed with water andsaturated sodium chloride, dried and concentrated in vacuo, giving anoil. Trituration with ligroin gave 45.0 g of2-[2-[4-(1,1dimethylethyl)phenyl]-1-thioxoethyl]thioglycolic acid.

A solution of 40 g of the above compound in 145 ml of 1N sodiumhydroxide with 18.1 g of methyl hydrazinocarboxylate was stirredovernight, then adjusted to pH 6 with 0.1N hydrochloric acid andextracted twice with dichloromethane. The extracts were combined, washedwith water, then saturated aqueous sodium chloride, dried andconcentrated in vacuo. The resulting oil was taken up in dichloromethaneand filtered through a bed of hydrous magnesium silicate withdichloromethane. The resulting oil was crystallized frommethylcyclohexane, giving 38.5 g of the desired compound as ivorycolored crystals, mp 93.5-94° C. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 90MHz: 1.30 (s, 9H, t-butyl); 3.74 (s, 3H, OCH₃); 4.04(s, 2H, CH₂ CS); [7.20 (d, 2H, J =8.0Hz) and 7.38 (d, 2H) (C₆ H₄)]; 8.54(bs, 1H, NH); 9.35 (bs, 1H, NH).

EXAMPLE 7 2-[2-(4-Methoxyphenyl)-1-thioxoethyl]hydrazine-carboxylicacid, methyl ester

A mixture of 200 g of 4-methoxyacetophenone, 214.5 g of piperidine and64.5 g of powdered sulfur was reacted as described in Example 6. Theproduct was further reacted with bromoacetic acid and hydrogen sulfideas described in Example 6, giving ethyl2-[2-(4-methoxyphenyl)-1-thioxoethyl]thioglycolate as an orange oil.

A mixture of 50 g of the above ester, 18.g. of methylhydrazinocarboxylate and 300 ml of dichloromethane was refluxed for 2hours, then washed twice with water, once with saturated sodium chlorideand dried. The resulting oily residue was concentrated under high vacuumat 50° C. for 2 hours and the semi-solid crystallized fromtoluene-hexane, giving 36 g of the desired compound as ivory coloredcrystals, mp 94.5-95° C. Proton nuclear magnetic resonance (δ[ppm],CDCl₃) 90MHz: 3.78 (s, 3H, OCH₃); 3.80 (s, 3H, OCH₃); 4.03 (s, 2H, CH₂CS); [6.89 (d, 2H, J=8.2Hz) and 7.21 (d, 2H)(C₆ H₄)]8.60 (bs, 1H, NH);9.40 (bs, 1H, NH).

EXAMPLE 82-[1-Thioxo-2-(3,4,5-trimethoxyphenyl)ethyl]-hydrazinecarboxylic acid,methyl ester

The procedure of Example 6 was repeated using3,4,5-trimethoxyacetophenone, giving2-[1-thioxo-2-(3,4,5-trimethoxyphenyl)ethyl]thioglycolic acid.

The above compound was reacted as described in Example 7, with methylhydrazinocarboxylate, giving an 85.0% yield of the desired product asivory crystals, mp 133.5-134° C. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 90MHz: 3.77 (s, 3H, OCH₃); 3.85 (s, 3H, OCH₃); 3.87 [s,6H, OCH₃ (2X)]; 4.04 (s, 2H, CH₂ CS); 6.52 (s, 2H, C₆ H₂); 8.51 (bs, 1H,NH); 9.15 (bs, 1H, NH).

EXAMPLE 9 2-[2-(2-Naththyl)-1-thioxoethyl]hydrazine

carboxylic acid, methyl ester

A mixture of 170.2 g of 2'-acetonaphthone, 51.2 g of sulfur and 136.2 gof piperidine was heated at reflux for 18 hours and then partitionedbetween dichloromethane and water. The aqueous phase was extracted twicewith dichloromethane. The aqueous phases were combined, washedsuccessively with 5% hydrochloric acid, twice with water and then withsaturated sodium chloride, dried and filtered through a bed of neutralalumina. The filtrate was concentrated to an oil which was taken up in700 ml of ether with stirring. This solution was stored in a chillroomovernight and the solid was collected, giving 125 g of1-[2-(2-naphthyl)-1-thioxoethyl]piperidine, mp 89°-91° C.

A 110 g portion of the above compound was stirred in 1.5 liters oftoluene, 61 g of bromoacetic acid was added and this mixture was stirredovernight. The supernatant was decanted, the residue dissolved in 500 mlof dichloromethane and one liter of ether added. The supernatant wasdecanted and the residue stirred with 300 ml of dichloromethane. Thesolid was collected, washed with ether and dried in vacuo, giving 54 gof 1-[1-[(carboxymethyl)thio]-2-(2-naphthyl)ethylidene]piperidiniumbromide, mp 140°-142° C.

A 40 g portion of the above compound was slurried in 500 ml ofisopropanol, hydrogen sulfide was bubbled into the mixture for 5 hours,then the mixture was allowed to stand overnight and concentrated invacuo. The residue was slurried in 500 ml of ether and filtered. Thefilter cake was washed with three 100 ml portions of ether. The filtrateand washings were combined and concentrated in vacuo, giving 23.5 g of2-[2-(2-naphthyl)-1-thioxoethyl]thioglycolic acid.

The 23.5 g of the above compound was slurried in 90 ml of 1N sodiumhydroxide, 130 ml of methanol was added followed by 11.0 g of methylhydrazinocarboxylate. This mixture was stirred for 3 hours, then dilutedwith 100 ml of water and the pH adjusted to 5.5. The mixture wasextracted twice with dichloromethane, the extracts combined, washed withwater and saturated sodium chloride, dried and filtered through hydrousmagnesium silicate. The filtrate was concentrated in vacuo, giving 21.3g of the desired product, mp 129°-131° C. Proton nuclear magneticresonance (δ[ppm], CDCl₃) 90MHz: 3.75 (s, 3H, OCH₃); 4.27 (s, 2H, CH₂CS); 7.30-8.00 (m, 7H, C₁₀ H₇); 8.55 (bs, 1H, NH); 9.50 (bs, 1H, NH).

EXAMPLE 10 2-[2-(2-Thienyl)-1-thioxoethyl]hydrazinecarboxylic acid,methyl ester

A mixture of 213 g of 2-thiophene acetic acid, 208.2 g of thionylchloride and one liter of benzene was stirred for 6 hours, thenconcentrated in vacuo. The residue was taken up in one liter of dryether, filtered and added dropwise to a cold solution of 301.7 g of drypiperidine and 1.5 liters of dry ether. This mixture was stirredovernight, then diluted with one liter of water and extracted threetimes with ether. The organic extracts were combined, washedsuccessively: (1) twice with 1N hydrochloric acid, (2) water, (3) twicewith 1N sodium hydroxide, (4) water and (5) saturated sodium chloride,and dried. The solution was passed through a bed of hydrous magnesiumsilicate with additional ether and then concentrated in vacuo. Theresulting oil was distilled, giving 250 g of N-(2-thienyl)acetylpiperidine, bp 132°-134° C. (0.5mmHg).

A mixture of 245 g of the above compound, 245.8 g of Lawesson's reagentand 850 ml of toluene was heated at 70°-78° C. for 12 hours, then cooledand concentrated in vacuo. The residue was taken up in 500 ml ofdichloromethane and percolated through a bed of basic alumina withadditional solvent. The resulting oil was crystallized fromtoluenecyclohexane, giving 245 g of N-[2-(2-thienyl)-1-thioxoethylpiperidine as light yellow needles, mp 51.5°-52° C.

A mixture of 112.7 g of the above compound, 06.5 g of iodomethane and100 ml of dry ether was stirred for 72 hours. The solid was collected,washed with dry ether and dried in vacuo, giving 175 g of 1-[1-(methyl-thio)-2-(2-thienyl)ethylidene]piperidinium iodide, mp 135°-140° C.

A suspension of 175 g of the above compound in 650 ml of dry methanolwas treated with gaseous hydrogen sulfide for 5 hours, then storedovernight and concentrated in vacuo. The residue was taken up in amixture of ether and water and the layers separated. The aqueous layerwas extracted with ether. The ether solutions were combined washed withsaturated sodium chloride, dried, concentrated and distilled, giving 75g of methyl 2-thiopheneethane(dithioate), bp 98.5-99.5 (0.4-0.5 mmHg) asan orange liquid.

A mixture of 70 g of the above compound, 36 g of methylhydrazinocarboxylate and 350 ml of dichloromethane was heated at refluxfor 2 hours, then cooled and diluted with 500 ml of ether. This solutionwas extracted three times with saturated aqueous sodium carbonate. Thealkaline extracts were combined and back extracted with ether. The etherextract was combined with the neutral organic solution and acidified topH 2. The acid solution was extracted three times with dichloromethane.The extracts were combined, washed with saturated sodium chloride, driedand concentrated in vacuo. A portion of this residue was purified bypreparative silica gel TLC, eluting with 1% methanol in dichloromethane.The resulting oil was crystallized from methylcyclohexane:diisopropylether (9:1), giving the desired product as yellow crystals, mp 74°-75°C. Proton nuclear magnetic resonance (δ[ppm], CDC13) 90MHz: 3.79 (s, 3H,OCH3); 4.30 (s, 2H, CH₂ CS); [7.00 (m, 2H) and 7.30 (m, 1H) (aromaticH's)]8.65 (bs, 1H, NH); 9.72 (bs, 1H, NH).

The non-alkaline soluble organic component was recovered andcrystallized from diisopropyl ether, giving yellow crystals, mp119.5°-121.5° C., of methyl[1-(methylthio)-2-(2-thienyl)ethylidene]hydrazinocarboxylate (Z isomer).Proton nuclear magnetic resonance (δ[ppm], CDCl₃) 90MHz: 2.45 (s, 3H);3.75 (s, 3H); 3.85 (s, 2H); [6.98 (m, 2H) and 7.25 (m, 1H) (aromaticH's)]; 7.25 (bs, 1H).

EXAMPLE 11 2-[2-(4-Chlorophenyl)-1-thioxoethyl]hydrazine -carboxylicacid, methyl ester

A mixture of 200 g of 4-chlorophenyl acetic acid, 178.5 g of thionylchloride and 600 ml of benzene was heated at reflux for 6 hours and thenconcentrated in vacuo. The residue was vacuum distilled, giving 215.8 gof 4-chlorophenyl acetyl chloride, bp 94°-95° C. (2.5 mmHg).

A solution of 120 g of dry pyridine, 103.2 g of piperidine and 1.5liters of dry ether was stirred vigorously as 215.7 g of freshlydistilled 4-chlorophenyl acetyl chloride in 250 ml of ether was addeddropwise. After 4 hours the mixture was diluted with one liter of waterand the organic phase collected. The aqueous phase was extracted withether and the ether phases were combined, washed successively with 0.1Nhydrochloric acid twice, 5% sodium hydroxide twice, saturated sodiumchloride twice, dried and concentrated in vacuo. The residual oil wastaken up in dichloromethane and percolated through a bed of neutralalumina with additional solvent. The resulting oil was crystallized fromcarbon tetrachloride:hexane (1:9), giving 243 g ofN-(4-chlorophenylacetyl)piperidine as yellow crystals, mp 85°-85.5° C.

A mixture of 200 g of N-(4-chlorophenylacetyl)piperidine, 94 g ofphosphorous pentasulfide and 750 ml of pyridine was heated at refluxwith vigorous stirring for 18 hours, then cooled and concentrated invacuo. The residue was taken up in 1.8 liters of water, heated at 50° C.for 30 minutes, cooled and exhaustively extracted with ether. The etherextracts were combined, washed successively with water, 5% hydrochloricacid twice and saturated sodium chloride and dried. The solution waspercolated through a bed of neutral alumina followed by elution withether. The resulting oil was crystallized twice from methylcyclohexane,giving 100 g of N-(4-chlorophenylthioacetyl)piperidine as orangecrystals, mp 82.5°-83.5° C.

A mixture of 200 g of N-(4-chlorophenylthioacetyl)piperidine, 117.5 g ofbromoacetic acid and 600 ml of benzene was stirred overnight, thendiluted with anhydrous ether and stirred overnight. The solid wascollected and dried in vacuo giving 241 g of1-[1-[(carboxymethyl)thio]-2-(4-chlorophenyl)ethylidene]piperidiniumbromide, mp 118-120° C.

A suspension of 181 g of the above compound in one liter of ethanol wastreated with gaseous hydrogen sulfide for 4 hours and then stored for 96hours. The suspension was concentrated in vacuo, then taken up in oneliter of anhydrous ether and filtered. The filtrate was washed withwater and saturated sodium chloride, dried and concentrated in vacuo.The resulting oil was crystallized from methylcyclohexane, giving 122.9g of 2-[2-(4-chlorophenyl)-1-thioxoethyl]thioglycolic acid, ethyl esteras yellow needles, mp 36.5°-37° C.

A mixture of 130 g of 2-[2-(4-chlorophenyl)-1-thioxoethyl]thioglycolicacid, ethyl ester, 45 g of methyl hydrazinocarboxylate and 500 ml ofdichloromethane was heated at reflux for 4 hours, then concentrated invacuo. The residue was taken up in 1.2 liters of ether and extractedwith three 500 ml portions of 0.5N sodium hydroxide. The alkalineextracts were combined, washed with ether and acidified with 6Nhydrochloric acid to pH 4. The solution was extracted three times with amixture of ether and dichloromethane. The organic phases were combinedand concentrated. The residual oil was concentrated at 70°-75° C. forone hour at 0.1 mmHg. The residue was crystallized fromacetone-methylcyclohexane and then from toluene, giving the desiredproduct as ivory colored crystals, mp 147.5°-148° C. Proton nuclearmagnetic resonance (δ[ppm], CDCl₃) 90MHz: 3.80 (s, 3H, OCH₃); 4.03 (s,2H, CH₂ CS); 7.31 (bs, 4H, C₆ H₄); 8.60 (bs, 1H, NH); 9.90 (bs, 1H, NH).

EXAMPLE 12 2-[2-(4-Fluorophenyl)-1-thioxoethyl]hydrazine

carboxylic acid, methyl ester

A well stirred mixture of 111.8 g of piperidine, 103 g of pyridine andone liter of anhydrous ether was treated dropwise with 220 g of freshlydistilled 4-fluorophenyl acetyl chloride. This mixture was stirredovernight, then filtered and the filtrate washed successively with watertwice, 0.1N sodium hydroxide twice, 0.1N hydrochloric acid twice, waterand saturated sodium chloride, then dried in vacuo. The residue wasdistilled giving a yellow liquid which crystallized on standing, giving245 g of N-(4-fluorophenylacetyl)piperidine.

A mixture of 210 g of the above compound, 104 g of phosphorouspentasulfide and 800 ml of pyridine was heated at reflux with stirringfor 4 hours, then cooled and concentrated in vacuo. The residue wastaken up in one liter of cold water, heated to 40° C. for 15 minutes,cooled and extracted three times with ether. The ether extracts werecombined and filtered through a bed of neutral alumina. The filtrate wasevaporated in vacuo and the residual liquid vacuum distilled. Thedistillate was crystallized from toluene-ether, giving 165 g ofN-(4-fluorophenylthioacetyl)piperidine, mp 65.5-67.5° C.

A mixture of 118.6 g of the above compound, 76.2 g of bromoacetic acidand 600 ml of benzene was stirred for 24 hours, then 2 liters of etherwas added. The suspension was stirred overnight and the solid collected,giving 150.2 g of1-[1-[(carboxymethyl)thio]-2-(4-fluorophenyl)ethylidene]piperidiniumbromide, mp 118°-119.5° C.

The above compound was reacted with hydrogen sulfide in ethanol asdescribed in Example 11, giving2-[2-(4-fluorophenyl)-1-thioxoethyl]thioglycolic acid, ethyl ester.

A mixture of 91.5 g of the above compound,36 g of methylhydrazinocarboxylate and 400 ml of dichloromethane was refluxed for 4hours, then washed twice with water, once with saturated sodiumchloride, dried and evaporated in vacuo. The residue was concentratedunder high vacuum and recrystallized from toluene, giving 43 g of thedesired product as ivory crystals, mp 149.5°-151.5° C. Proton nuclearmagnetic resonance (δ[ppm], CDCl₃) 90MHz: 3.77 (s, 3H, OCH₃); 3.85 (s,3H, OCH₃); 3.87 [s, 6H, OCH₃ (2X)]; 4.04 (s, 2H, CH₂ CS); 6.52 (s, 2H,C₆ H₂); 8.51 (bs, 1H, NH); 9.15 (bs, 1H, NH).

EXAMPLE 13 2-[2-(3-Methoxyphenyl -1-thioxoethyl]hydrazine

carboxylic acid methyl ester

A 200 g portion of 3-methoxyacetophenone was added dropwise withstirring over a one hour period to a mixture of 181 g of piperidine and68.2 g of sulfur. This mixture was heated at 130° C. overnight, thenconcentrated in vacuo. The resulting oil was partitioned betweendichloromethane and water. The aqueous layer was separated and extractedtwice with dichloromethane. All organic phases were combined, washedwith 5% hydrochloric acid, then twice with water and finally withsaturated sodium chloride. The solution was filtered through a neutralalumina pad, the filtrate concentrated in vacuo and the residue slurriedin 600 ml of ether and stored in a chill room. The solid was collectedand dried in vacuo, giving 56 g of1-[2-(3-methoxyphenyl)-1-thioxoethyl]piperidine as yellow crystals, mp55°-56° C.

A mixture of 49.8 g of the above compound, 30.6 g of bromoacetic acidand 600 ml of toluene was stirred overnight and then diluted with 1.2liters of ether. The solid was collected, washed with ether and dried invacuo, giving 36.4 g of1-[1-[(carboxymethyl)thio]-2-(3-methoxyphenyl)ethylidene]piperidiniumbromide, mp 149°-151° C.

A 51 g portion of1-[1-(carboxymethyl)thio]-2-(3-methoxyphenyl)ethylidene]piperidiniumbromide was slurried in 450 ml of isopropanol. Gaseous hydrogen sulfidewas bubbled in for 4.5 hours, then the mixture was allowed to stand 48hours and concentrated in vacuo. The residue was slurried in 200 ml ofether and filtered. The filter cake was washed three times with ether.The filtrate and washings were combined, concentrated in vacuo, theresidue dissolved in 250 ml of ether and extracted with two 300 mlportions of 0.3N sodium hydroxide. The alkaline extracts were combined,acidified, extracted into dichloromethane, dried and concentrated invacuo, giving 22 g of [[2-(3-methoxyphenyl)-1-thioxoethyl]thio]aceticacid, mp 93°-95° C.

A 20 g portion of the above compound was slurried in 80 ml of 1N sodiumhydroxide, 10.5 g of methyl hydrazinocarboxylate was added followed by100 ml of methanol. This mixture was stirred for 4 hours, poured into100 ml of water, the pH adjusted to 4.5 and the mixture extracted threetimes with dichloromethane. The extracts were combined, washed withwater, then saturated sodium chloride, dried and filtered through a bedof hydrous magnesium silicate. The filtrate was concentrated to an oilwhich was crystallized from cyclohexane, giving the desired product asivory colored crystals, mp 56°-58° C. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 90MHz: 3.78 (s, 3H, OCH₃); 3.82 (s, 3H, OCH₃); 4.04 (s,2H, CH₂ CS); [6.90 (m, 3H) and 7.30 (dd, 1H, J =8.0Hz; 8.0Hz)(C₆ H₄)];8.65 (bs, 1H, NH); 9.80 (bs, 1H, NH).

EXAMPLE 14 2-[1-Thioxo-2-[3-(trifluoromethyl)phenyl]ethyl]

hydrazinecarboxylic acid, methyl ester

A suspension of 95 g of 3-(trifluoromethyl)phenylacetic acid in 500 mlof dry benzene was treated with 71.4 g of thionyl chloride. Afterrefluxing for 4 hours the solvent was removed in vacuo and the residueazeotroped twice with toluene. A solution of this material in 250 ml ofether was used to treat a cold solution of 85 g of piperidine in 400 mlof ether. After 2 hours the reaction was diluted with 600 ml of waterand extracted three times with ether. The extracts were combined, washedtwice with saturated sodium chloride, dried and concentrated in vacuo.The resulting oil was vacuum distilled giving an oil, bp 136°-138° C.(0.9mmHg) which was crystallized from heptane giving 93 g of1-[[3-(trifluoromethyl)phenyl]acetyl]piperidine, mp 34.5°-35.5° C.

A mixture of 135.6 g of 1-[[3-(trifluoromethyl)phenyl]acetyl]piperidine,101.1 g of Lawesson's reagent and 400 ml of benzene was heated at refluxfor 6 hours, cooled and concentrated in vacuo. The residue was taken upin dichloromethane, filtered through a bed of neutral alumina with 3liters of dichloromethane elution. The filtrate was concentrated invacuo. The resulting oil was vacuum distilled giving 131 g of1-[1-thioxo-2-[3-(trifluoromethyl) phenyl]ethyl]piperidine, bp 181°-182°C. (3.0 mmHg).

A solution of 125 g of the above compound in 400 ml of benzene wastreated with 75.2 g of ethyl bromoacetate. After standing 2 hours, themixture was diluted with 500 ml of dry ether and filtered. The filtercake was washed with dry ether and dried in vacuo, giving 150 g of1-[1-[(2-ethoxy-2-oxoethyl)thio]-2-[3-(trifluoromethyl)phenyl]ethylidene]piperidiniumbromide as a white solid, mp 129°-132° C.

A suspension of 145 g of the above compound in 500 ml of dry ethanol wastreated with gaseous hydrogen sulfide for 40 minutes, then storedovernight and concentrated in vacuo. The residue was suspended in 700 mlof ether and filtered. The filtrate was washed with ether until allyellow color was absent, then concentrated in vacuo and vacuumdistilled, giving 80 g of[[1-thioxo-2-[3-(trifluoromethyl)phenyl]ethyl]thio]acetic acid, ethylester, bp 177°-178° C. (5.0-5.5mmHg).

A solution of 64.5 g of the above compound, 22.5 g of methylhydrazinocarboxylate and 400 ml of dichloromethane was heated at refluxfor 4 hours, cooled and then diluted with 600 ml of dichloromethane. Thesolution was washed with water (thrice), and saturated sodium chloride(twice), dried and concentrated in vacuo. The residue was taken up indichloromethane, filtered through a bed of hydrous magnesium silicatewith additional solvent and the filtrate evaporated. The solid wascrystallized from toluene, giving 56 g of the desired product as yellowcrystals, mp 131°-132.5° C. Proton nuclear magnetic resonance (δppm],CDCl₃) 90MHz: 3.80 (s, 3H, OCH₃); 4.10 (s, 2H, CH₂ CS); 7.55 (m, 4H, C₆H₄); 8.55 (bs, 1H, NH); 9.90 (bs, 1H, NH).

EXAMPLE 15 2-(3-Ethoxy-3-oxo-1-thioxopropyl)hydrazinecarboxylic acid,methyl ester

A mixture of 1-[(ethoxycarbonyl)acetyl]piperidine, 131 g of phosphoruspentasulfide and one liter of toluene was stirred for 96 hours. Thesolvent was decanted and saved. The gum was washed with 250 ml oftoluene. The toluene solutions were combined and concentrated in vacuo.The residue was dissolved in dichloromethane and percolated through abed of hydrous magnesium silicate, washing with the same solvent. Thefiltrate and wash were combined and concentrated in vacuo, giving 92 gof ethyl 3-thioxo-N-piperidinepropionate.

A solution of 92 g of the above compound, 65.5 g of methyl bromoacetateand 300 ml of benzene was stirred for 96 hours. The resulting crystalswere collected, washed with cold benzene and dried in vacuo, giving 115g of1-[1-(2-methoxy-2-oxoethyl)thio]-2-[(ethoxycarbonyl)ethylidene]piperidiniumbromide, mp 92°-94° C.

A mixture of 110 g of the above compound and 500 ml of methanol wastreated with gaseous hydrogen sulfide until 1.2 equivalents were takenup. The mixture was kept overnight and then concentrated in vacuo. Theresidue was taken up in ether, filtered, washed with ether and thefiltrate and wash combined, concentrated in vacuo and vacuum distilled,giving [1-thioxo-2-[(ethoxycarbonyl)ethyl]thio]acetic acid, methyl esteras a liquid, bp 136°-138° C., (4 mmHg).

A mixture of 49 g of the above compound, 19.9 g of methylhydrazinocarboxylate an 400 ml of dichloromethane was heated at refluxfor 5 hours, then washed with water, saturated sodium chloride, driedand concentrated in vacuo to an oil. The oil was further concentrated athigh vacuum. The residue was taken up in dichloromethane andchromatographed on a column of silica gel packed in the same solvent.The column was eluted with 2 liters of dichloromethane and then 2 litersof ether. The desired fractions were combined and worked up, giving 30 gof the desired compound as a yellow oil. Proton nuclear magneticresonance (δ[ppm], CDCl₃) 90MHz: 1.30 (t, 3H, CH₃ CH₂ O); 3.87 (s, 3H,OCH3); 3.91 (s(3H, CH2CS); 4.27 (q, 2H, OCH₂ CH₃); 8.85 (bs, 1H, NH);11.52 (bs, 1H, NH).

EXAMPLE 16 2 -[2-(Phenylthio)-1-thioxoethyl]hydrazinecarboxylic acid,methyl ester

A suspension of 168.5 g of thiophenoxyacetic acid, 750 ml of benzene and142.7 g of thionyl chloride was heated at reflux for 10 hours, thenconcentrated in vacuo. The residue was taken up in 500 ml of dry etherand added dropwise to a cold, stirred solution of 189.2 g of pyridine in1.7 liters of dry ether. After 6 hours, water was added and the twophases separated. The aqueous phase was extracted twice with ether, allorganic phases were combined, washed successively with 5% sodiumhydroxide twice, water, 1N hydrochloric acid twice, water and saturatedsodium chloride, then dried and concentrated in vacuo. The residue wascrystallized from methylcyclohexane, giving 211 g of2-[2-(phenylthio)acetyl]piperidine, mp 68.5°-69.5° C.

A mixture of 117.6 g of the above compound, 102 g of Lawesson's reagentand 750 ml of toluene was heated at 80° C. for 12 hours, then cooled,percolated through a bed of hydrous magnesium silicate and eluted withdichloromethane. The filtrate was concentrated in vacuo giving an oilwhich was crystallized from cyclohexane, giving 115 g of1-[1-thioxo-2-[2-(phenylthio)]ethyl]piperidine, mp 83°-84° C.

A solution of 110 g of the above compound, 67 g of methyl bromoacetateand 450 ml of benzene was stirred overnight, then filtered. The filtercake was washed with cold 2-butanone until ivory colored, then dried invacuo, giving 165 g of1-[1-[(2-methoxy-2-oxoethyl)thio]-2-[(phenylthio)methyl]ethylidene]piperidiniumbromide, mp 165°-170° C.

A mixture of 160 g of the above compound and 600 ml of dry methanol wastreated for 4 hours with gaseous hydrogen sulfide, then stored overnightand the solvent removed in vacuo. The residue was taken up in 400 ml ofether and filtered. The filter cake was washed with ether untilcolorless. The filtrate and washings were combined, concentrated invacuo, taken up in dichloromethane and filtered through a bed of hydrousmagnesium silicate with dichloromethane elution. Evaporationgave[1-thioxo-2-[2-(phenylthio)ethyl]thio]acetic acid, methyl ester as aliquid.

A mixture of 91 g of the above compound, 36 g of methylhydrazinocarboxylate and 300 ml of dichloromethane was heated at refluxfor 3 hours and then diluted with 600 ml of ether. This solution wasextracted three times with saturated sodium carbonate. The alkalineextracts were combined, washed with ether, acidified to pH 2 andextracted twice with dichloromethane. The organic extracts werecombined, washed with water and saturated sodium chloride, dried andconcentrated in vacuo, giving an oil. This oil was dissolved indichloromethane, percolated through a bed of hydrous magnesium silicatewith the same solvent and evaporated, giving 50.2 g of the desiredcompound as a yellow oil. Proton nuclear magnetic resonance(δ[ppm],CDCl₃) 90MHz: 3.79 (s, 3H, OCH₃); 4.18 (s, 2H, SCH₂ CS); 7.32(bs, 5H, C₆ H₅); 8.55 (bs, 1H, NH); 10.55 (bs, 1H, NH).

EXAMPLE 17 2-[2-(Tetrahydro-2H-pyran-2-yl)-1-thioxoethyl]

hydrazinecarboxylic acid, methyl ester

2-[2-(Tetrahydro-2H-pyran-2-yl)]acetic acid was reacted as described inExample 16, giving 2-[2-[(tetrahydro-2H-pyran-2-yl)-1-thioxo]thio]aceticacid, ethyl ester.

A mixture of 78.7 g of the above compound, 29.3 g of methylhydrazinocarboxylate and 400 ml of dichloromethane was stirredovernight, then evaporated in vacuo. The residue was taken up in 250 mlof dichloromethane and percolated through a bed of magnesium trisilicatewith the same solvent. The filtrate was concentrated in vacuo, thenunder high vacuum (0.2 mm Hg), giving an oil. This oil was crystallizedfrom diisopropyl ether at 0° C., giving 64.5 g of the desired product asivory colored crystals, mp 109.5-110.520 C. Proton nuclear magneticresonance (δ[ppm], CDCl₃) 300MHz: 1.35-1.85 [m, 6H, (CH₂)3CH₂ O]; 2.92(m, 2H, CHCH₂ CS); 3.55 (m, 2H, CH₂ O); 3.79 (s, 3H, OCH₃); 4.10 (m, 1H,CHCH₂); 8.72 (bs, 1H, NH); 10.98 (bs, 1H, NH).

EXAMPLE 18 2-(Aminocarbonyl)hydrazide benzenepropanethioic acid

Phenylthiopropionylpiperidine was converted to[(3-phenyl-1-thioxopropyl)thio]acetic acid, ethyl ester by the generalprocedure of Example 16, using ethyl bromoacetate.

A solution of 50 g of the above compound in 400 ml of ethanol wastreated with a solution of 25.1 g of semicarbazide hydrochloride and18.5 g of anhydrous sodium acetate in 150 ml of water. After 2 hours themixture was concentrated in vacuo, the residue taken up in 400 ml oftoluene and stored at 5° C. for 12 hours. The solid was collected,washed with toluene and dried in vacuo, giving 35 g of the desiredcompound as white crystals, mp 118°-119° C. Proton nuclear magneticresonance (δ[ppm], CDCl₃) 90MHz 2.95 (m, 2H, CH₂); 3.12 (m, 2H, CH₂);4.79 (bs, 2H, NH₂); 7.28 (bs, 5H, C₆ H₅); 8.83 (bs, 1H, NH); 9.75 (bs,1H, NH).

EXAMPLE 19 2-(Aminocarbonyl)hydrazide propanethioic acid

A solution of thiopropionylpiperidine in 700 ml of dry ether was treatedwith ethyl bromoacetate. The mixture was stored for 26 hours, then thesolid was collected, washed with ether and dried in vacuo. This solidwas dissolved in 1100 ml of anhydrous ethanol and treated with gaseoushydrogen sulfide. After 12 hours the mixture was concentrated in vacuo,the suspension taken up in one liter of ether and filtered. The filtercake was washed with ether until no yellow color remained. The filtrateand wash were combined and concentrated in vacuo, giving a liquid whichwas distilled, giving [(1-thioxopropyl)thio]acetic acid, ethyl ester asa light orange oil, bp 105°-107° C. (2 mmHg).

A solution of 78.1 g of semicarbazide hydrochloride in 500 ml of ethanolwas treated with 57.4 g of anhydrous sodium acetate. After 30 minutes asolution of 118.2 g of the above compound was added, the reaction washeated at 70°-75° C. for 4 hours and then concentrated in vacuo. Theresidue was suspended in 800 ml of dichloromethane, stirred vigorouslyfor 10 minutes and the solvent decanted. The gum was taken up in 500 mlof ethyl acetate and 1500 ml of ethanol and filtered. The filtrate wasconcentrated in vacuo. The filter cake was boiled three times with 700ml portions of ethanol. These extracts were combined with the aboveconcentrate and evaporated. The residue was crystallized fromethanol-ethyl acetate, giving 46 g of the desired compound as whitecrystals, mp 136°-137° C. Proton nuclear magnetic resonance (δ[ppm],CDCl₃) 90MHz: 1.20 (t, 3H, CH₃); 2.60 (q, 2H, CH₂ CS); 5.70 (bs, 2H,NH₂); 9.33 (bs, 1H, NH); 11.33 (bs, 1H, NH).

EXAMPLE 20 2-(Aminocarbonyl)hydrazide butanethioic acid

[(1-Thioxobutyl)thio]acetic acid, ethyl ester was prepared by theprocedure of Example 19, using 1-thiobutylpiperidine.

A mixture of 250 g of semicarbazide hydrochloride, anhydrous sodiumacetate, 250 g of the above compound and 1.2 liters of water was stirredovernight and then concentrated in vacuo. The residue was taken up in900 ml of water and extracted three times with ethyl acetate. Theextracts were combined, washed with water twice, then saturated sodiumchloride, dried and concentrated in vacuo. The residue was crystallizedfrom ethyl acetate-t-butyl methyl ether, giving 150.6 g of the desiredcompound as white crystals, mp 134.5°-136° C. Proton nuclear magneticresonance (δ[ppm], CDCl₃) 90MHz: 0.95 (t, 3H, CH₃); 1.80 (m, 2H, CH₂CH₃); 2.64 (t, 2H, CH₂ CS); 5.85 (bs, 2H, NH₂); 9.27 (bs, 1H, NH); 11.27(bs, 1H, NH).

EXAMPLE 21 3-(1,2,3-Thiadiazol-4-ylthio)propanoic acid, methyl ester

A 4.6 g portion of ethyl caroazate was carefully added to 50 ml ofacetic anhydride producing an exotherm. The reaction was heated on asteam bath for one hour, then evaporated to an oil. The oil wascrystallized from chloroform giving acetyl carbazate ethyl ester.

The above compound was reacted with phosphorous pentachloride on a steambath, then evaporated to an oil which was crystallized from chloroform.

To a cold solution of the above compound in tetrahydrofuran was added acold solution of the sodium salt of 3-mercaptopropionic acid, methylester in methanol. After standing at room temperature for several hoursthe mixture was filtered. The filtrate was evaporated to dryness, theresidue dissolved in ethyl acetate, filtered and the filtrate evaporatedto an oil. This oil was added to 25 ml of thionyl chloride, allowed tostand 1/2 hour and then evaporated to dryness. The residue wasevaporated twice from dichloromethane, then dissolved in ethyl acetateand washed with saturated sodium bicarbonate, water and brine, thendried and evaporated to dryness. The residue was chromatographed on 600ml of silica gel, eluting with ethyl acetate:hexane (1:2), collecting200 ml fractions. The third fraction was then chromatographed onpreparative silica gel plates eluting with acetone, giving 841 mg of thedesired compound as a light orange oil. Proton nuclear magneticresonance (δ[ppm], CDCl₃) 90MHz: .76 (t, 2H, J=6.5Hz, CH₂ CO₂); 3.48 (t,2H, SCH₂); 3.71 (s, 3H, CH₃ O); 8.33 (s, 1H, H-5).

EXAMPLE 22 3-(1,2,3-Thiadiazol-4-ylthio)propanoic acid, ethyl ester

One mole of methyl magnesium bromide in ether was diluted with one literof dry tetrahydrofuran. The ether was removed by distillation and thetetrahydrofuran solution kept at 45° C. as 80 g of carbon disulfide wasadded dropwise. When addition was complete the mixture was heated at50°-55° C. for one hour, then 140 g of ethyl 3-bromopropionate was addeddropwise. The reaction was then heated at reflux for 4 hours, cooledovernight and diluted with one liter of water. The mixture was washedsuccessively with ether (thrice), water (twice) and saturated sodiumchloride, then dried and evaporated. The residual liquid was vacuumdistilled, giving 70 g of ethyl 3-[(1-thioxoethyl)thio]propionate as ayellowish orange liquid, bp 82°-84° C. (0.5 mmHg).

A mixture of 9 g of the above compound, 12.5 g of methylhydrazinocarboxylate and 300 ml of chloroform was heated at reflux for 3hours, cooled and concentrated in vacuo. The oily residue was thenconcentrated at 70° C., 2mm Hg for one hour, then dissolved in 400 ml ofether and washed twice with water. The organic phase was dried andconcentrated in vacuo, giving 2-(1-thioxoethyl)hydrazinecarboxylic acid,methyl ester as a viscous orange oil.

A mixture of 29.6 g of the above compound, 50 ml of ethyl acrylate, 5 mlof triethylamine, and 300 ml of benzene was heated at reflux for 12hours and concentrated in vacuo. The crude oil was chromatographed overhydrated magnesium trisilicate with dichloromethane and the desiredfractions pooled. The yellow oil was crystallized from diisopropyl etherto yield 45.0 g of(Z)-[1-[(3-ethoxy-3oxopropyl)thio]ethylidene]hydrazinecarboxylic acid,methyl ester.

A mixture of 2.5 g of the above compound, 20 ml of thionyl chloride and10 ml of dry dichloromethane was heated at reflux for 3 hours, thenconcentrated in vacuo. The residual oil was taken up in dichloromethaneand filtered through a bed of hydrous magnesium silicate with the samesolvent. The resulting oil was purified by preparative TLC on silicagel, eluting with dichloromethane, giving 907 mg of the desired compoundas a yellowish orange oil. Proton nuclear magnetic resonance (δ[ppm],CDCl₃) 90MHz: 1.28 (t, 3H, J =7.0Hz, CH₃); 2.79 (t, 2H, J =6.5Hz, CH₂CO₂); 3.48 (t, 2H, SCH₂); 4.16 (q, 2H, OCH₂); 8.35 (s, 1H, 5-H).Infrared spectrum (neat): 3120(m); 1740(s); 1260-1125(s); 948-885.

EXAMPLE 23 3-[(5-Methyl-1,2,3-tniadiazol-4-yl)thio]propanoic acid, ethylester

A suspension of 73.6 g of 2-(aminocarbonyl)hydrazide propanethioic acidin 750 ml of dry acetone was treated with 69.3 g of anhydrous potassiumcarbonate. After stirring for 30 minutes, 14.2 g of freshly preparedethyl 3-iodopropionate was added, then the mixture was heated at reflux,cooled and concentrated to 1/2 volume. One liter of water was added andthe mixture was extracted twice with dichloromethane. The extracts werecombined, washed with water, 5% sodium chloride, dried and evaporated invacuo. The residual oil was purified by chromatography on silica gel.The oil was applied with dichloromethane and eluted with the samesolvent. The solvent system was then changed to a 2-5% gradient ofmethanol in dichloromethane. The active fractions were combined,concentrated to an oil and crystallized from diisopropyl ether, giving3-[[1-[(aminocarbonyl)hydrazono]propyl]thio]propanoic acid, ethyl esteras white needles, mp 63.5°-64.5° C.

A solution of 49.4 g of the above compound was reacted with thionylchloride as described in Example 22, giving the desired compound as alight yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl₃)90MHz 1.26 (t, 3H, J=7.0Hz, CH₃ CH₂); 2.55 (s, 3H, CH₃); 2.70 (t, 2H,J=7.0Hz, CH₂ CO); 3.39 (t, 2H, SCH₂); 4.14 (q, 2H, OCH₂ CH₃). Infraredabsorption spectrum (neat) 1735(s); 1460(w); 1420(w); 1370(m); 1342(m);1285(m); 1245(m); 1218(m); 1170(m); 1140(m); 1045(m); 1040(m); 1025(m);1010(m); 890(m).

EXAMPLE 24 3-[(5-Ethyl-1,2,3-thiadiazol-4-yl)thio]propanoic acid, ethylester

3-[[1-[(Aminocarbonyl)hydrazono]butyl]thio]propanoic acid, ethyl esterwas prepared from 2-(aminocarbonyl)hydrazide butanethioic acid asdescribed in Example 23.

A 130.7 g portion of the above compound was reacted with thionylchloride as described in Example 22, giving 83 g of the desired compoundas a light yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl₃)90MHz: 1.27 (t, 3H, J=7.2Hz, CH₃ CH₂ O); 1.36 (t, 3H, J=7.0Hz, CH₃ CH₂2.73 (t, 2H, CH₂ CO); 2.96 (q, 2H, CH₂ C=); 3.43 (t, 2H, SCH₂). Infraredabsorption spectrum (neat) 1735(s); 1460(w); 1415(w); 1370(m); 1342(w);1285(w); 1245(w); 1220(w); 1170(m); 1140(m); 1045(m); 1025(m); 1010(m);890(m)

EXAMPLE 25 3-[[5-(1,1-Dimethylethyl -1,2,3-thiadiazol-4-yl]

thio]propanoic acid, methyl ester

A mixture of 20.5 g of 2-(3,3-dimethyl-1-thioxobutyl)hydrazinecarboxylicacid, methyl ester, 12.92 g of methyl acrylate, 1 ml of triethylamineand 300 ml of dry benzene was heated at reflux for 8 hours, then cooledand concentrated in vacuo. The residual oil was chromatographed througha bed of hydrous magnesium silicate, eluting with dichloromethane andevaporated, giving 27 g of(Z)-[1-[(3-methoxy-3-oxopropyl)thio]-3,3-dimethylbutylidene]hydrazinecarboxylicacid, methyl ester.

A solution of 29 g of the above compound, 17.9 g of thionyl chloride and300 ml of benzene was heated at reflux for 18 hours, then cooled andconcentrated in vacuo. The oily residue was taken up in 500-600 ml ofether, washed with 2% sodium hydroxide twice, water and saturated sodiumchloride, dried and concentrated in vacuo. The residue was dissolved inbenzene, applied to a column of silica gel packed in petroleum ether andeluted with 1.5 liters of benzene, followed by 1.5 liters of 5% ethylacetate in petroleum ether. The desired fractions were combined andevaporated, giving 17.5 g of the desired compound as a light orange oil.Proton nuclear magnetic resonance (δ[ppm], CDCl₃) 90MHz: 1.51 (s, 9H,t-butyl); 2.85 (t, 2H, J=6.5Hz, CH₂ CO); 3.60 (t, 2H, SCH₂); 3.70 (s,3H, OCH₃). Infrared absorption spectrum (neat): 1735(s); 1460 (m);1430(m); 1400(m); 1355(m); 1245(m); 1210(m); 1170(m); 1150(m); 925(m).

EXAMPLE 26 3-[[5-(1,1-Dimethylethyl)-1,2,3-thiadiazol-4-yl]

thio]propanoic acid, ethyl ester

A mixture of[1-[(3-ethoxy-3-oxopropyl)thio]-3,3-dimethylbutylidene]hydrazinecarboxylicacid, methyl ester, thionyl chloride and dichloromethane was heated atreflux for 40 hours and then quenched with ice water. The orange productwas extracted twice into ether. The extracts were combined, washed with0.1N sodium hydroxide twice, water twice, saturated sodium chloridetwice, dried and concentrated in vacuo. The resulting orange liquid wasevaporated onto 70 g of silica gel. The gel was dried and poured onto acolumn of silica gel packed in petroleum ether. The column was elutedwith a gradient of 1-10% ethyl acetate in petroleum ether. The desiredfractions were purified on silica gel preparative TLC plates elutingwith 3% ethyl acetate in petroleum ether, giving 2.9 g of the desiredcompound as a light yellow oil. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 90MHz: 1.23 (t, 3H, J =7.0Hz, CH₃); 1.49 (s, 9H,t-butyl); 2.84 (t, 2H, J =7.0Hz, CH₂ CO); 3.59 (t, 2H, SCH₂); 4.14 (q,2H, OCH₂).

EXAMPLE 27 3-[(5-Phenyl-1,2,3-thiadiazol-4-yl)thio]propanoic acid, ethylester

[1-[(3-Ethoxy-3-oxopropyl)thio]-2-(phenyl)ethylidene]hydrazinecarboxylicacid, methyl ester was prepared from2-(2-phenyl-1-thioxoethyl)hydrazinecarboxylic acid, methyl ester.

A mixture of 16.2 g of the above compound, 23.6 g of thionyl chlorideand 100 ml of dry dichloromethane was heated at reflux for 3 hours andthen concentrated in vacuo. The residue was taken up in a mixture ofether and dichloromethane, washed three times with water, then saturatedsodium chloride, dried and concentrated to an oil. This oil was purifiedon a silica gel column, eluting with dichloromethane. The desiredfractions were combined and worked up giving 12.5 g of the desiredcompound as white cubes, mp 57.5-58.5° C. Proton nuclear magneticresonance (δ[ppm], CDCl₃) 90MHz: 1.22 (t, 3H, J=7.0Hz, CH₃); 2.76 (t,2H, J=6.5Hz, CH₂ CO); 3.52 (t, 2H, SCH₂); 4.08 (q, 2H, OCH₂); 7.53 (bs,5H, C₆ H₅). Infrared absorption spectrum (KBr pellet): 1740(s); 1225(s);1195(s); 1175(s); 1155 (s); 1 1015(s); 932(s); 758(s); 685-690(s).

EXAMPLE 28 3-[[5-(4-Methylphenyl)-1,2,3-thiadiazol-4-yl]

thio]propanoic acid, ethyl ester

A mixture of 30 g of2-[2-(4-methylphenyl)-1-thioxoethyl]hydrazinecarboxylic acid, methylester, 25 g of ethyl acrylate, 500 μl of triethylamine and 250 ml ofbenzene was heated at reflux for 24 hours, cooled and concentrated invacuo. The resulting oil was purified by dry column chromatography onsilica gel, eluting with dichloromethane. The desired fractions werecollected and evaporated, giving[1-[(3-ethoxy-3-oxopropyl)thio]-2-(4-methylphenyl)ethylidene]hydrazinecarboxylicacid, methyl ester as an oil.

A solution of 28 g of the above compound, 23.8 g of thionyl chloride and125 ml of dry dichloromethane was heated at reflux for 5 hours, thenpoured into ice. This mixture was extracted three times with ether. Theextracts were combined, washed successively with water twice, 5% aqueoussodium bicarbonate twice, water and saturated sodium chloride, dried andevaporated. The resulting oil was purified on a silica gel dry column,eluting with dichloromethane. The active fraction was concentrated underhigh vacuum, giving an oil. This oil was crystallized frommethylcyclohexane at 20° C., giving the desired product as ivory coloredneedles, mp 68.5°-69.5° C. Proton nuclear magnetic resonance (δ[ppm],CDCl₃) 90MHz: 1.22 (t, 3H, J=7.0Hz, CH₃); 2.42 (s, 3H, CH₃ C₆ H₄); 2.80(t, 2H, J=7.5Hz, CH₂ CO₂); 3.58 (t, 2H, SCH₂); 4.15 (q, 2H, OCH₂); [7.27(d, 2H, J =8.0Hz) and 7.50 (d, 2H)(C₆ H₄)]. Infrared absorption spectrum(KBr pellet): 1735(s); 1518(w); 1480(w); 1460(w); 1440(w); 1412(w);1400(w); 1365(w); 1230(m); 1200(s); 1160(m); 1021(m); 935(m); 820(m).

EXAMPLE 293-[[5-[4-(1,1-Dimethylethyl)phenyl]-1,2,3-thiadiazol-4-yl]thio]propanoicacid, ethyl ester

A mixture of 35 g of2-[2-[4-(1,1-dimethylethyl)phenyl]-1-thioxoethyl]hydrazinecarboxylicacid, methyl ester, 20.2 g of ethyl acrylate, 1.0 ml of triethylamineand 250 ml of benzene was heated at reflux for 28 hours and thenconcentrated in vacuo. The resulting oil was purified over a dry columnof silica gel, eluting with dichloromethane. The active fractions werecombined and evaporated giving 45.2 g of a 2/1 mixture of [Z(andE)]-[2-[4-(1,1-dimethylethyl)phenyl]-1-[(3-ethoxy-3-oxopropyl)thio]ethylidene]hydrazinecarboxylicacid methyl ester as a faint yellow oil.

A 40 g portion of the above mixture, 250 ml of dry dichloromethane and26.9 g of thionyl chloride were mixed, heated at reflux for 3 hours andthen poured into ice. The mixture was extracted three times with ether.The extracts were combined, washed twice with water, twice with 5%aqueous sodium bicarbonate, water and saturated sodium chloride, driedand evaporated. The resulting oil was purified by dry columnchromatography on silica gel, eluting with dichloromethane. The desiredfractions were pooled and concentrated, giving 27.6 g of the desiredproduct as an orange oil. Proton nuclear magnetic resonance (δ[ppm],CDCl₃) 90MHz: 1.24 (t, 3H, J =7.0Hz, CH₃); 1.32 (s, 9H, t-butyl); 2.83(t, 2H, J =6.5Hz, CH₂ CO₂); 3.60 (t, 2H, SCH3); 4.15 (q, 2H, OCH₃); 7.55(s, 4H, C₆ H₄). Infrared absorption spectrum (neat): 1740 (s); 1610(m);1522(m); 1375(m); 1270(m); 1250(m); 1220(m); 1200(m); 1180(m); 935(s);840(s).

EXAMPLE 30 3-[[5-(4-Methoxyphenyl)-1,2,3-thiadiazol-4-yl]

thio]propanoic acid, ethyl ester

A mixture of 50.9 g of2-[2-(4-methoxyphenyl)-1-thioxoethyl]hydrazinecarboxylic acid, methylester, 30 g of ethyl acrylate, 2 ml of triethylamine and 450 ml ofbenzene was heated at reflux for 27 hours, then cooled and concentratedin vacuo. The resulting oil was purified as described in Example 29,giving [Z(andE)]-[1-[(3-ethoxy-3-oxopropyl)thio]-2-(4-methoxyphenyl)ethylidene]hydrazinecarboxylicacid, methyl ester.

A 52.4 g portion of the above compound, 29.8 g of thionyl chloride and300 ml of dichloromethane were mixed, stirred for 5 hours and thenpoured onto chipped ice. This mixture was extracted three times withether. The extracts were combined, washed with water, twice with 1%sodium hydroxide, twice with water, saturated sodium chloride, dried andevaporated. The resulting oil was purified on a dry column of silicagel, eluting with 1.5 liters of 10% ethyl acetate in hexane. The desiredfraction was evaporated to an oil which was crystallized fromdiisopropyl ether at 0°-5° C., giving 25 g of the desired product asivory colored needles, mp 50.5°-51.5° C. Proton nuclear magneticresonance (δ[ppm], CDCl₃) 90MHz: 1.21 (t, 3H, J =7.0Hz, CH₃); 2.78 (t,2H, J =7.0Hz, CH₂ CO); 3.51 (t, 2H, SCH₂); 3.85 (s, 3H, OCH₃); 4.12 (q,2H, OCH₂); [6.99 (d, 2H, J=9.0Hz) and 7.55 (d, 2H, (C₆ H₄)]. Infraredabsorption spectrum: 1735(s); 1615(m); 1520(m); 1480(m); 1465(w);1445(w); 1418(w); 1400(w); 1370(w); 1355(w); 1265(m); 1225(m); 1205(m);1180(m); 1155(m); 1035(m); 1018(m); 830-840(m).

EXAMPLE 313-[[5-(3,4,5-Trimethoxyphenyl)-1,2,3-thiadiazol-4-yl]thio]propanoicacid, ethyl ester

A mixture of2-[1-thioxo-2-(3,4,5-trimethoxyphenyl)ethyl]hydrazinecarboxylic acid,methyl ester, ethyl acrylate, triethylamine and benzene was treated asdescribed in Example 30, giving [Z(andE)]-[1-[(3-ethoxy-3-oxopropyl)thio]-2-(3,4,5-trimethoxyphenyl)ethylidene]hydrazinecarboxylicacid, methyl ester.

A 13.8 g portion of the above mixture was reacted as described inExample 30 and purified by chromatography, eluting with dichloromethane.The resulting oil was crystallized from diethyl ether, giving 5.6 g ofthe desired product as ivory needles, mp 27°-27.5° C. Proton nuclearmagnetic resonance (δ[ppm], CDCl₃) 90MHz: 1.24 (t, 3H, J=7.0Hz, CH₃);2.82 (t, 2H, J=6.5Hz, CH₂ CO₂); 3.60 (t, 2H, SCH₃); 3.91 s, 9H, OCH₃'s); 4.15 (q, 2H, OCH₂); 6.81 (s, 2H, C₆ H₂). Infrared absorptionspectrum (KBr pellet): 1735(s); 1580(s); 1515(s); 1470(s); 1415(s);1330(s); 1250(s); 1180(m); 1130(s).

EXAMPLE 32 3-[[5-(2-Naphthyl)-1,2,3-thiadiazol-4-yl]thiopropanoic acid,ethyl ester

A solution of 20 g of2-[2-(2-naphthyl)-1-thioxoethyl]hydrazinecarboxylic acid, methyl ester,1 ml of triethylamine, 12 g of ethyl acrylate and 200 ml of toluene washeated at 80° C., then concentrated. The residue was taken up in 500 mlof dichloromethane, passed through hydrous magnesium silicate, treatedwith charcoal, filtered through sodium sulfate and concentrated invacuo. The resulting oil was dissolved in 50 ml of toluene, stored in achill room overnight and concentrated in vacuo to an oil. This oil waspurified on a dry silica gel column, eluting with heptane:ethyl acetate(1:1). The desired fraction was collected, dissolved in dichloromethane,passed through an alumina pad and evaporated, giving [E(andZ)]-2-[1-[(3-ethoxy-3-oxopropyl)thio]-2-(2-naphthyl)ethylidene]hydrazinecarboxylicacid, methyl ester.

A 13 g portion of the above mixture was dissolved in 80 ml ofdichloromethane. A solution of 8.6 g of thionyl chloride in 40 ml ofdichloromethane was added dropwise with stirring. The mixture wasstirred 2.5 hours, then heated at 70° C. for 3 hours, allowed to standover night, poured onto 400 g of crushed ice and stirred for one hour.The aqueous layer was extracted twice with dichloromethane. All organicsolutions were combined, washed with saturated sodium bicarbonate, waterand saturated sodium chloride, dried, passed through a bed of neutralalumina and concentrated in vacuo to an oil. The oil was crystallizedfrom diethyl ether, giving 3.6 g of the desired product as ivorycrystals, mp 46.5°-47.5° C. Proton nuclear magnetic resonance (δ[ppm],CDCl₃) 90MHz: 1.23 (t, 3H, J=7.0Hz, CH₃); 2.84 (t, 2H, J=7.0Hz, CH₂CO₂); 3.60 (t, 2H, SCH₂); 4.13 (q, 2H, OCH₂); 7.45-8.25 (m, 7H, C₁₀ H₇).

EXAMPLE 33 3-[[5-(2-Thienyl)-1,2,3-thiadiazol-4-yl]thio]propanoic acid,ethyl ester

A mixture of 45.6 g of 2-[(2-thienyl)-1-thioxoethyl]hydrazinecarboxylicacid, methyl ester, 50.0 g of ethyl acrylate, 500 ml of benzene, and 5ml of triethylamine was heated at reflux for 18 hours and concentratedin vacuo. The oily residue was taken up into dichloromethane andpercolated through a bed of hydrated magnesium trisilicate withdichloromethane. The desired fractions of [Z(andE)]-[1-[(3-ethoxy-3-oxopropyl)thio]-2-(2-thienyl)ethylidene]hydrazinecarboxylicacid, methyl ester were pooled and concentrated to yield 54.7 g ofyellow oil.

A mixture of 32.9 g of the above compound, 25 g of thionyl chloride, and500 ml of dichloromethane was allowed to stand for 6 hours, and pouredonto ice and extracted with dichloromethane. The combined extracts wereworked up as in Example 32 to yield 21.0 g of orange oil. Proton nuclearmagnetic resonance (δ[ppm], CDCl₃) 90MHz: 1.24 (t, 3H); 2.83 (t, 2H);3.61 (t, 2H); 4.14 (q, 2H); [6.97 (dd, 1H) and 7.41 (m, 2H) aromaticH's].

EXAMPLE 34 3-[[5-(4-Chlorophenyl)-1,2,3-thiadiazol-4-yl]thio]propanoicacid, ethyl ester

A mixture of 29.5 g of2-[2-(4-chlorophenyl)-1-thioxoethyl]hydrazinecarboxylic acid, methylester, 20.5 g of ethyl acrylate, 300 ml of benzene and 1 ml oftriethylamine was heated at reflux for 18 hours and then concentrated invacuo. The oily residue was chromatographed on a dry column of silicagel, eluting with dichloromethane. The desired fractions were combinedand treated as described in Example 30, giving 20.5 g of [Z(andE)]-[1-[(3-ethoxy-3-oxopropyl)thio]-2-(4-chlorophenyl)ethylidene]hydrazinecarboxylicacid, methyl ester.

A mixture of 11.92 g of the above compound, 9 g of thionyl chloride and200 ml of dichloromethane was allowed to stand for 15 hours, then pouredonto ice and extracted twice with ether. The extracts were combined,washed with 0.1N sodium hydroxide twice, water and saturated sodiumchloride, dried and evaporated. The resulting oil was dissolved indichloromethane and evaporated onto 50 g of silica gel. This silica gelwas poured onto a column of silica gel packed in petroleum ether andthen eluted under slight pressure, with a gradient of 0-20% ethylacetate in petroleum ether giving an oil. This oil was crystallized fromdiisopropyl ether, giving 8.3 g of the desired compound as ivory cubes,mp 71.5°-73.5° C. Proton nuclear magnetic resonance (δ[ppm], CDCl₃)90MHz: 1.24 (t, 3H, J=7.0Hz, CH₃); 2.78 (t, 2H, J=7.0Hz, CH₂ CO₂); 3.56(t, 2H, SCH2); 4.10 (q, 2H, OCH2); 7.50 (A₂ B₂ quartet, 4H, C₆ H₄).Infrared absorption spectrum (KBr pellet): 1725(s); 1590(w); 1400(w);1370(w); 1280(w); 1250(w); 1220(m); 1175(m); 1150(m); 1090(m); 1010(m);930(m); 830(m).

EXAMPLE 35 3-[[5-(4-Fluorophenyl)-1,2,3-thiadiazol-4-yl]-thio]propanoicacid, ethyl ester

A mixture of 36.3 g of2-[2-(4-fluorophenyl)-1thioxoethyl]hydrazinecarboxylic acid, methylester, 20 g of ethyl acrylate, 250 ml of benzene and 1 ml oftriethylamine was heated at reflux for 18 hours, cooled and concentratedin vacuo. The oily residue was taken up in dichloromethane, filteredthrough a bed of diatomaceous earth with additional solvent andevaporated in vacuo. The residual oil was chromatographed on a drycolumn of silica gel, eluting with dichloromethane. The active fractionswere combined and concentrated in vacuo, giving [Z(andE)]-[1-[(3-ethoxy-3-oxopropyl)thio]-2-(4-fluorophenyl)ethylidene]hydrazinecarboxylicacid, methyl ester as a colorless oil.

A solution of 28 g of the above compound, 20.3 g of thionyl chloride and150 ml of dichloromethane was reacted as described in Example 34, giving20.6 g of the desired product as ivory needles, mp 76.5°-77.5° C. Protonnuclear magnetic resonance (δ[ppm], CDCl₃) 90MHz: 1.23 (t, 3H, J=7.0Hz,CH₃); 2.80 (t, 2H, J=7.0Hz, CH₂ CO₂); 3.56 (t, 2H, SCH₂); 4.13 (q, 2H,OCH₂); [7.20 (dd, 2H, J_(H-F) =8.0Hz; J_(H-H) =8.0Hz) and 7.61 (dd, 2H,J_(H-F) =5.5Hz) (C₆ H₄)]. Infrared absorption spectrum (KBr pellet):1730(s); 1605(w); 1520(m); 1475(m); 1440(w); 1410(w); 1375(w); 1355(w);1255(w); 1240(m); 1220(m); 1200(m); 1050 (w); 1020(w); 930(m); 830(m).

EXAMPLE 36 3-[[5-(3-Methoxyphenyl)-1,2,3-thiadiazol-4-yl]thio]propanoicacid, ethyl ester

[1-[(3-Ethoxy-3-oxopropyl)thio]-2-(3-methoxyphenyl)ethylidene]hydrazinecarboxylicacid, methyl ester was prepared from2-[2-(3-methoxyphenyl)-1-thioxoethyl]hydrazinecarboxylic acid, methylester.

A mixture of the 36.3 g of the above compound in dichloromethane wastreated with 25.0 g of thionyl chloride, stored at 30° C. for 8 hoursand then poured onto chipped ice. The product was extracted three timeswith ether. The extracts were combined, washed with water twice, 0.1Nsodium hydroxide twice, water, saturated sodium chloride and dried. Thesolution was evaporated onto silica gel which was poured onto a silicagel column and eluted with a gradient of 0°-15% ethyl acetate in hexane.The desired fractions were combined to give 18.0 g of the desiredcompound as a light orange oil. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 90MHz: 1.23 (t, 3H, J=7.0Hz, CH₃); 2.79 (t, 2H, J=7.0Hz,CH₂ CO₂); 3.55 (t, 2H, SCH₂); 3.82 (s, 3H, OCH₃); 4.10 (q, 2H, OCH₂);6.80-7.55 (m, 4H, C₆ H₄). Infrared absorption spectrum (neat): 1725(s);1590(m); 1575(m); 1495(m); 1458(m); 1450(m); 1420(m); 1370(m); 1345(m);1295 (m); 1280(m); 1245(m); 1185(m); 1160(m); 1051(m); 1006(m); 936(m);860(m); 780(m).

EXAMPLE 373-[[5-[3-(Trifluoromethyl)phenyl]-1,2,3-thiadiazol4-yl]thio]propanoicacid, methyl ester

A suspension of 29.3 g of2-[1-thioxo-2-[3-(trifluoromethyl)phenyl]ethyl]hydrazinecarboxylic acid,methyl ester, was reacted with methyl acrylate, triethylamine andbenzene as described in Example 35, giving [Z(andE)]-[1-[(3-methoxy-3-oxopropyl)thio]-2-[3-(trifluoromethyl)phenyl]ethylidene]hydrazinecarboxylicacid, methyl ester.

A solution of 37.8 g of the above compound in 250 ml of dichloromethanewas treated with 18 g of thionyl chloride. After standing for 3 hoursthe solvent was removed in vacuo, the residue taken up in ether, washedwith 0.1N sodium hydroxide twice, then saturated sodium chloride, driedand evaporated on 125 g of silica gel. This silica gel was poured onto acolumn of silica gel packed in petroleum ether and then eluted with agradient of 0°-10% ethyl acetate in petroleum ether, giving 17.5 g ofthe desired product as an orange oil. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 90MHz: 2.86 (t, 2H, J=7.0Hz, CH₂ CO₂); 3.57 (t, 2H,SCH₂); 3.66 (s, 3H, OCH₃); 7.55-7.85 (m, 4H, C₆ H₄).

EXAMPLE 38 3-[[5-Phenylmethyl)-1,2,3-thiadiazol-4-yl]thio]propanoicacid, methyl ester

A suspension of 22.4 g of 2-(aminocarbonyl)hydrazidebenzenepropanethioic acid in 300 ml of dry benzene was treated with 25ml of methyl acrylate followed by 1 ml of triethylamine. After 2 hoursthe solution was concentrated in vacuo, the resulting oil was taken upin dichloromethane and chromatographed on silica gel, eluting with thesame solvent. The desired fractions were combined and concentrated invacuo, giving 27.9 g of(Z)-3-[[1-[(aminocarbonyl)hydrazinone]-3-phenylpropyl]thio]propanoicacid, methyl ester as a yellow oil.

A solution of 20.7 g of the above compound in 150 ml of choroform wasreacted with thionyl chloride as described in Example 22, giving 10 9 ofthe desired compound as an orange oil. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 90MHz: 2.85 (t, 2H, J =7.0Hz, CH₂ CO₂); 3.57 (t, 2H,SCH₂); 3.65 (s, 3H, OCH₃); 4.31 (s, 2H, CH₂ C₆ H₅); 7.30 (m, 5H, C₆ H₅).Infrared absorption spectrum (neat) 1735(s); 1495(w); 1435(m); 1355(m);1245(s); 1220(m); 1200(m); 1170(m); 705(m).

EXAMPLE 39 3-[[5-(Phenylthio)-1,2,3-thiadiazol-4-yl]thio]propanoic acid,ethyl ester

A solution of 40 g of2-[2-(phenylthio)-1-thioxoethyl]hydrazinecarboxylic acid, methyl ester,20.5 g of ethyl acrylate, 2 ml of triethylamine and 300 ml of benzenewas heated at reflux for 12 hours, then cooled and concentrated invacuo. The residue was dissolved in dichloromethane, filtered throughhydrous magnesium silicate, washing with the same solvent and evaporatedto an oil, giving 33.5 g of [Z(andE)]-[1-[(3-ethoxy-3-oxopropyl)thio]-2-(phenylthio)ethylidene]hydrazinecarboxylicacid, methyl ester.

A 33 g portion of the above compound and thionyl chloride in 250 ml ofdichloromethane was allowed to stand for 6 hours, then poured into iceand extracted three times with ether. The extracts were combined, washedwith 0.1N sodium hydroxide twice, water, saturated sodium chloride,dried and evaporated onto 100 g of neutral alumina. The alumina wasapplied to a column of neutral alumina packed in petroleum ether. Thecolumn was eluted with a gradient of 0°-10% ethyl acetate in petroleumether. The active fractions were combined giving 28 g of the desiredproduct as an orange oil. Proton nuclear magnetic resonance (δ[ppm],CDCl₃) 90MHz: 1.27 (t, 3H, J =7.2Hz, CH₃ CH₂ O); 2.79 (t, 2H, J=7.0Hz,CH₂ CO₂); 3.44 (t, 2H, SCH₂); 4.17 (q, 2H, OCH₂); 7.40-7.70 (bs, 5H, C₆H₅). Infrared absorption spectrum (neat): 1735(s); 1575(m); 1475(m);1435(m); 1385(m); 1370(m); 1345(m); 1210(s); 1185(s); 1150(s); 1055(m);1020(m); 930-925(m); 750(s); 690(s).

EXAMPLE 40(Racemic)-3-[[5-(Tetrahydro-2H-pyran-2-yl)-1,2,3-thiadiazol-4-yl]thio]propanoicacid, methyl ester

2-[2-(Tetrahydro-2H-pyran-2-yl)-1-thioxoethyl]hydrazinecarboxylic acid,methyl ester was converted to [Z(andE)]-[1-[(3-methoxy-3-oxopropyl)thio]-2-[(3-tetrahydro-2H-pyran-2-yl)ethylidene]hydrazinecarboxylicacid, methyl ester as described in Example 35.

The above compound was reacted as described in Example 37, giving thedesired product as an orange oil. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 300MHz: 1.50-2.20 [m, 6H, (CH₂)₃ CH₂ O];2.80 (t, 2H,J=7.0Hz, CH₂ CO₂); 3.45-3.60 (m, 2H, CH₂ O); 3.55 (t, 2H, SCH₂); 3.70(s, 3H, CH₃ O); 5.22 (dd, 1H, J =7.0Hz; 6.0Hz, CHO). Infrared absorptionspectrum (neat): 1742(s); 1440(s); 360(s); 1295(m); 1245(m); 1220(m);1200(m); 1170(m); 150(m); 935(m).

EXAMPLE 41 4-(Ethylthio)-1,2,3-thiadiazole

A mixture of 54.1 g of methyl hydrazinecarboxylate, 61.8 g of distilledethyl dithioacetate and 500 ml of chloroform was heated at reflux for 3hours, then evaporated in vacuo. The residue was dissolved in 500 ml ofether:dichloromethane (1:1), washed with water twice, then saturatedsodium chloride, dried and concentrated in vacuo. The residue wassuspended in cold hexane:ether (1:1) and the solid collected andrecrystallized from methylcyclohexane, giving 53 g of [Z(andE)]-[1-(ethylthio)ethylidene]hydrazinecarboxylic acid, methyl ester asivory colored needles mp 87°-88.5° C.

A solution of 1.8 g of the above compound in 10 ml of drydichloromethane was treated with 5 ml of thionyl choride, allowed tostand 3 hours and concentrated in vacuo. The resulting oil was dissolvedin a small amount of dichloromethane and applied to six 2000μ×20cm×20cmsilica gel preparative TLC plates. The plates were eluted withdichloromethane and the active band worked up to give a red oil. Thisoil was taken up in a small amount of dichloromethane and filteredthrough neutral alumina with the same solvent, giving 295 mg of thedesired product as a light yellow oil. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 90MHz: 1.38 (t, 3H, J=7.0Hz, CH₃); 3.17 (q, 2H, SCH₃);8.25 (s, 1H, H-5). Infrared absorption spectrum (neat): 3120(m);1415(s); 1265-1245(s); 1210(s); 950(s); 884(s); 820-720(m).

EXAMPLE 42 5-(1,1-Dimethylethyl)-4-(phenylthio)-1,2,3-thiadiazole

A solution of 65.5 g of hydrazinecarboxylic acid, methyl ester, 150 mlof dry pyridine and 500 ml of dry dichloromethane was stirred at 0° C.and 100 g of distilled t-butylacetyl chloride was added dropwise. After2 hours at 0°-5° C. the solvent was removed in vacuo. The residue wastaken up in 1.2 liters of ethyl acetate, washed with saturated sodiumchloride and filtered through a bed of hydrous magnesium silicate withadditional ethyl acetate. The filtrate was concentrated and the solidrecrystallized from diisopropyl ether, giving 130 g of2-(3,3-dimethyl-1-oxobutyl)hydrazinecarboxylic acid, methyl ester aswhite platelets, mp 83°-84.5° C.

A solution of 23 g of the above compound, 26.1 g of phosphorouspentachloride and 250 ml of chloroform containing 5 drops ofdimethylformamide was heated at reflux for 4 hours, then cooled andconcentrated in vacuo. The oily residue was azeotropically distilledtwice with toluene under vacuum, then dissolved in 150 ml of drytetrahydrofuran and added dropwise to a freshly prepared suspension ofsodium thiophenoxide in tetrahydrofuran. After 3 hours the solution wasconcentrated in vacuo, the residue dissolved in 500 ml of water andextracted three times with ethyl acetate. The extracts were combined,washed with 0.1N sodium hydroxide twice, then saturated sodium chlorideand dried. The resulting oil was dissolved in petroleum ether, appliedto a chromatographic column on a Waters Prep 500A and eluted with 4.5liters of petroleum ether to remove low polarity components. The columnwas then eluted with 4 liters of 1% methanol in dichloromethane, giving17.5 g of [Z(andE)]-[3,3-dimethyl-1-(phenylthio)butylidene]hydrazinecarboxylic acid,methyl ester as a light orange oil.

A solution of 14 g of the above compound, 8.85 g of thionyl chloride and250 ml of chloroform was heated at reflux for 8 hours, then cooled andconcentrated in vacuo. The resulting oil was dissolved in a small amountof benzene and applied to a column of silica gel packed in benzene. Theactive fractions were collected, giving 8.8 g of the desired product asa yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl₃) 90MHz:1.58 (s, 9H, t-butyl); 7.29 (bs, 5H, C₆ H₅). Infrared absorptionspectrum (neat): 1585(m); 1480(s); 1442(m); 1370(m); 1250(m); 1219(m);1180(m); 1028(w) 926(s); 745(m); 710(s); 695(s).

EXAMPLE 43 5-Phenyl-4-(phenylthio)-1,2,3-thiadiazole

A mixture of 43.8 g of phosphorous pentachloride in 350 ml of drydichloromethane was treated dropwise with a solution of 44.5 g of2-(phenyl-1-oxoethyl)hydrazinecarboxylic acid, methyl ester in 200 ml ofdry dichloromethane. After refluxing for 6 hours, the solvent wasremoved in vacuo and the residue was azeotropically distilled twice with350 ml portions of toluene. The residue was then dissolved in 200 ml ofdry tetrahydrofuran and saved.

A suspension of 4.7 g of sodium hydride in 350 ml of dry tetrahydrofuranwas treated dropwise with 6.75 g of dry methanol, then 23.2 g ofthiophenol was added. After one hour the tetrahydrofuran solution ofcrude hydrazonyl chloride was added dropwise at 0°-5° C. over a 30minute period. After 2 hours at room temperature the solvent was removedin vacuo and the mixture was partitioned between ethyl acetate andwater. The aqueous layer was extracted twice with ethyl acetate, allorganic layers were combined, washed with saturated sodium chloride anddried. The resulting oil was evaporated onto 125 g of silica gel. Thissilica gel was applied to a column of silica gel packed in petroleumether and eluted with a gradient of 0°-50% ethyl acetate in petroleumether. The desired fractions were collected giving an oil which wascrystallized from isopropyl ether, giving 40 g of(Z)-[2-phenyl-1-phenylthio)ethylidene]hydrazinecarboxylic acid, methylester as yellow needles, mp 67.5°-70° C.

A solution of (Z)-[2-phenyl-1-(phenylthio)ethylidene]hydrazinecarboxylicacid, methyl ester in 450 ml of dry dichloromethane was treated with29.7 g of thionyl chloride. This mixture ws refluxed for one hour, thenpoured into chipped ice and extracted three times with ether. Theextracts were combined, washed with 0.1N sodium hydroxide twice, waterand saturated sodium chloride and dried. This material was evaporatedonto 100 g of silica gel which was then poured onto a column of silicagel packed in petroleum ether. The column was eluted with a gradient of20°-60% dichloromethane in petroleum ether, giving 35 g of the desiredcompound as an orange oil. Proton nuclear magnetic resonance (δ[ppm],CDCl₃) 90MHz: 7.28 (bs, 5H, C₆ H₅); 7.30-7.65 (m, 5H, C₆ H₅). Infraredabsorption spectrum (neat): 1580(m); 1475(s); 1440(s); 1286(w); 1265(m);1255(m); 1240(w); 1025(w); 1005(w); 985(w); 935(m); 915(m); 805(m);765(m); 745(s); 695(s).

EXAMPLE 44 4-(Methylthio)-1,2,3-thiadiazole-5-carboxylic acid, ethylester

A mixture of 107.5 g of freshly distilled ethyl3-thioxo-N-piperidinepropionate, 100.0 g of iodomethane and 500 ml ofanhydrous ether was stirred for 24 hours. The solid was collected,washed with ether and dried in vacuo, giving 155 g of1-[1-(methylthio)]-2-[ethoxycarbonyl]ethylidene]piperidinium iodide.

A suspension of 140 g of the above compound in 450 ml of anhydrousethanol was treated with gaseous hydrogen sulfide for 5 hours, thenallowed to stand 24 hours. The solvent was removed in vacuo, the residuesuspended in 700 ml of dry ether and filtered. The filter cake waswashed with ether, the wash and filtrate combined and concentrated invacuo and then distilled giving 67.7 g of2-(ethoxycarbonyl)ethane(dithioic acid), methyl ester as an orangeliquid, bp 91-92° C. (0.1 mmHg).

A mixture of 35.8 g of the above compound, 19.81 g ofhydrazinecarboxylic acid, methyl ester and 250 ml of dichloromethane washeated at reflux for 8 hours, then concentrated in vacuo. The resultingoil was taken up in ether:dichloromethane (1:1), washed twice withwater, dried and concentrated in vacuo. This residue was dissolved inether, 56.4 g of methyl iodide was added, the mixture stored for 48hours and then concentrated in vacuo. The oily residue was dissolved in75 ml of acetone, 280 ml of 1N sodium carbonate was added and thismixture was extracted three times with ether. The extracts werecombined, and worked up giving 55.0 g of [E(andZ)]-[1-(methylthio)-2-(ethoxycarbonyl)ethylidene]hydrazinecarboxylicacid, methyl ester as an orange oil.

A solution of 16 g of the above compound in 150 ml of dichloromethanewas treated with 17.9 g of thionyl chloride, allowed to stand 4 hours,poured onto ice and then extracted three times with ether. The extractswere combined, washed with water, 0.1N sodium hydroxide and water andthen concentrated in vacuo. The resulting oil was purified on a flashchromatography column of alumina, eluting with a 0-10% ethyl acetate inpetroleum ether gradient. The active fractions were combined,concentrated in vacuo and crystallized from diisopropyl ether, giving7.0 g of the desired product as white cubic crystals, mp 64.5°-65.5° C.Proton nuclear magnetic resonance (δ[ppm], CDCl₃) 90MHz: 1.37 (t, 3H,J=7.0Hz, CH₃ CH₂ O); 2.87 (s, 3H, SCH₃); 4.39 (q, 2H, OCH₂). Infraredabsorption spectrum (KBr pellet): 1710(s); 1470(w); 1440(w); 1430(w);1365(w); 1320(w); 1305(s); 1175(s); 1085(s); 1010(m); 970(m).

EXAMPLE 45 4-(Methylthio)-5-(2-thienyl)-1,2,3-thiadiazole

2-[2-(2-Thienyl)-1-thioxoethyl]hydrazinecarboxylic acid, methyl esterwas chromatographed on silica gel, eluting with dichloromethane giving[E(and Z)]-[1-(methylthio)-2-(2-thienyl)ethylidene]hydrazinecarboxylicacid, methyl ester.

A solution of 24.4 g of the above compound in 150 ml of dichloromethanewas stirred with 25.0 g of thionyl chloride. After 3 hours the mixturewas poured onto ice and basified to pH 9 with 0.1N sodium hydroxide.This suspension was extracted with dichloromethane twice, the extractscombined, dried and concentrated in vacuo. The resulting oil was takenup in 250 ml of dichloromethane, evaporated onto silica gel which wasthen applied to a column of silica gel packed in petroleum ether andeluted with a gradient of 0-20% dichloromethane in petroleum ether. Thedesired fractions were pooled and evaporated, giving an oil which wascrystallized from diisopropyl ether, giving 11 g of the desired productas yellow crystals, mp 49°-49.5° C. Proton nuclear magnetic resonance(67 [ppm], CDCl₃) 90MHz: 2.85 (s, 3H, SCH₃); [6.96 (dd, 1H) and 7.41 (m,2H) (C₄ H₃ S)]. Infrared absorption spectrum (KBr pellet): 1435(m);1420(m); 1390(s); 1352(m); 1250(s); 1220(m); 1195(m); 1160(m); 920(m);705(s).

EXAMPLE 46 5-(4-Methoxyphenyl)-4-(methylthio)-1,2,3-thiadiazole

A mixture of 70.7 g of (4-methoxyphenyl)ethanedithioic acid, methylester, 31.0 g of hydrazinecarboxylic acid, methyl ester, and 500 ml ofdichloromethane was heated at reflux for 8 hours, and then concentratedin vacuo. The resulting oil was taken up in dichloromethane and appliedto a column of silica gel. The column was eluted with a gradient of 0-2%methanol in dichloromethane and the desired fractions pooled andconcentrated. The yellow liquid was used as obtained.

A mixture of.55 g of [E(andZ)]-[1-(methylthio)-2-(4-methoxyphenyl)ethylidene]hydrazinecarboxylicacid, methyl ester in 350 ml of dichloromethane was treated with 29.5 gof thionyl chloride. This mixture was allowed to stand for 10 hours,then poured onto ice and extracted thrice with dichloromethane. Theextracts were combined, washed with 2% sodium hydroxide twice, water andsaturated sodium chloride, dried and evaporated. The residue wascrystallized from diisopropyl ether, giving 40.5 g of the desiredproduct as off-white needles, mp 60.5°-61° C. Proton nuclear magneticresonance (δ[ppm], CDCl₃) 90MHz: 2.81 (s, 3H, SCH₃); 3.86 (s, 3H, OCH₃);[7.02 (d, 2H, J=9.0Hz) and 7.57 (d, 2H)(C₆ H₄)]. Infrared absorptionspectrum (KBr pellet): 1605(m); 1515(m); 1460(w); 1450(w); 1435(m);1400(m); 1300(m); 1265(m); 1245(s); 1210 (w); 1175(m); 1022(s); 930(m);830(s).

EXAMPLE 474-(Methylthio)-5-[3-(trifluoromethyl)phenyl]-1,2,3-thiadiazole

A solution of 11.6 g of3-[[5-[3-(trifluoromethyl)phenyl]-1,2,3-thiadiazol-4-yl]thio]propanoicacid, methyl ester in 100 ml of dry methanol was treated with 32 ml of1M methanolic sodium methoxide. After standing one hour, the solvent wasremoved in vacuo, the residue taken up in dry methanol, filtered andthen concentrated. The oil was triturated with ether giving a solidwhich was collected and dried in vacuo, giving 6.8 g of5-[3-(trifluoromethyl)phenyl]-1,2,3-thiadiazole-4-thiol, monosodium saltas a yellow powder, mp>200° C.

A solution of 5.69 g of the above compound in 25 ml of methanol wastreated with 7.1 g of methyl iodide. After standing for 2 hours, thesolvent was removed in vacuo, the residue taken up in 75 ml ofdichloromethane and filtered through a bed of hydrous magnesium silicatewith additional solvent. The filtrate was evaporated giving the desiredcompound as a light orange oil. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 90MHz 2.85 (s, 3H, SCH₃); 7.45-8.00 (m, 4H, C₆ H₄).Infrared absorption spectrum (neat): 1495(w); 1430(w); 1415(w); 1325(s);1250(s); 1170(s); 1125(s); 1070(m); 1005(w); 935(m); 895(m); 800(m);695(m).

EXAMPLE 48 [5-(4-Methylphenyl)-1,2,3-thiadiazol-5-yl]thio]acetic acid,ethyl ester

A suspension of 13.8 g of3-[[5-(4-methylphenyl)1,2,3-thiadiazol-4-yl]thio]propanoic acid, ethylester in 250 ml of dry ethanol was treated with 200 ml of 1M potassiumethoxide in ethanol. After standing 1.5 hours, the solvent was removedin vacuo to about 100 ml and 400 ml of anhydrous ether was added. Thesolid was collected, washed with ether, dissolved in methanol andfiltered. The filtrate was concentrated to a small volume and thendiluted with 400 ml of anhydrous ether. The solid was collected anddried in vacuo, giving 11.5 g of5-(4-methylphenyl)1,2,3-thiadiazole-4-thiol, monopotassium salt as ayellow solid, mp>125° C. (dec.).

A solution of 4.92 g of the above compound in 50 ml of dry methanol wastreated with 3.45 g of ethyl bromoacetate, stirred for 12 hours and thesolvent removed in vacuo. The residue was suspended in ether, filteredand washed with ether. The combined filtrate and wash was concentratedin vacuo, giving an oil. This oil was taken up in dichloromethane andevaporated onto 20 g of silica gel. This gel was poured onto a drycolumn of silica gel and then eluted with 15% ethyl acetate in hexane.The desired fraction was concentrated giving an oil which wascrystallized from petroleum ether, giving 5 g of the desired product asivory cubes, mp 60°-60.5° C. Proton nuclear magnetic resonance (δ[ppm],CDCl₃) 90MHz: 1.21 (t, 3H, J=7.0Hz, CH₃); 2.42 (s, 3H, CH₃); 4.10 (s,2H, SCH₂); 4.17 (q, 2H, CH₂ O); [7.32 (d, 2H, J=8.0Hz) and 7.55 (d,2H)(C₆ H₄)]. Infrared absorption spectrum (KBr pellet): 1736(s);1515(w); 1475(w); 1440(w); 1400(w); 1380(w); 1370(w); 1315(s); 1290(w);1250(w); 1225(w); 1175(s); 1168(s); 1025(m); 930(m); 815(m).

EXAMPLE 495-[4-(1,1-Dimethylethyl)phenyl]-4-(ethylthio)1,2,3-thiadiazole

A solution of 15.9 g of3-[[5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazol-4-yl]thio]propanoicacid, ethyl ester in 75 ml of anhydrous ethanol was treated with 105 mlof 0.5M potassium ethoxide in ethanol. After 3 hours the solvent waspartially removed in vacuo and 200 ml of anhydrous ether was added. Theresulting solid was collected, washed with ether, redissolved inmethanol, filtered and the filtrate concentrated to 10-15 ml. A 250 mlportion of anhydrous ether was added and the solid was collected anddried in vacuo, giving 13 g of5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazol-4-thiol, potassium saltas a yellow solid, mp>150° C.

A mixture of 865 mg of the above compound in 25 ml of ethanol wastreated with 940 mg of ethyl iodide, then stirred for one hour andconcentrated in vacuo. The residue was taken up in ether, filtered andconcentrated to an oil. This oil was purified on thick layerchromatography plates, eluting with dichloromethane, giving 755 mg ofthe desired compound as a yellow oil. Proton nuclear magnetic resonance(δ[ppm], CDCl₃) 90MHz: 1.37 (s, 9H, t-butyl); 1.39 (t, 3H, J=7.0Hz,CH₃); 3.35 (q, 2H, SCH₃); 7.54 (s, 4H, C₆ H₄). Infrared absorptionspectrum (neat): 1610(w); 1520(w); 1475(w); 1460(w); 1445(w); 1405(w);1365(w); 1270(s); 1175(s); 936(s); 820(s).

EXAMPLE 505-[4-(1,1-Dimethylethyl)phenyl]-4-(2-propenylthio)-1,2,3-thiadiazole

A solution of 1.45 g of5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol, potassiumsalt in 50 ml of ethanol was stirred overnight with 3.0 g of allylbromide. The solvent was removed in vacuo, the residue taken up inether, filtered and concentrated in vacuo. The residual oil wasdissolved in a small amount of dichloromethane and purified on thicklayer silica gel plates, eluting with the same solvent. The activefraction gave 1.225 g of the desired compound as a yellow oil. Protonnuclear magnetic resonance (δ[ppm], CDCl₃) 90MHz: 1.39 (s, 9H, t-butyl);3.98 (bd, 2H, SCH₂); 5.05 (bd, 1H, CH=); 5.20 (bd, 1H, =CH); 5.87 (m,1H, CH₂ CH=); 7.55 (s, 4H, C6H4). Infrared absorption spectrum (neat):1640(w); 1615(w); 1525(w); 1480(w); 1475(w); 1450(w); 1410(w); 1370(w);1270(w); 930(s); 820(s).

EXAMPLE 51[[5-[4-(1,1-Dimethylethyl)phenyl]-1,2,3-thiadiazol-4-yl]thio]acetic acidethyl ester

A solution of 2.9 g of5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol, potassiumsalt in 50 ml of ethanol was stirred overnight with 1.67 g of ethylbromoacetate, then concentrated in vacuo. The residue was taken up inether, filtered and evaporated in vacuo. The oily residue was dissolvedin dichloromethane and purified as described in Example 50, giving anoil which was crystallized from methylcyclohexane, giving 2.8 g of thedesired compound as white needles, mp 62.5°-63.5° C. Proton nuclearmagnetic resonance (δ[ppm], CDCl₃) 90MHz: 1.21 (t, 3H, J=7.0Hz, CH₃);1.37 (s, 9H, t-butyl); 4.11 (s, 2H, SCH₂); 4.15 (q, 2H, CH₂ O); 7.55 (s,4H, C₆ H₄). Infrared absorption spectrum (KBr pellet): 1739(s); 1606(w);1520(w); 1480(w); 1445(w); 1385(w); 1365(w); 1305(s); 1175(s); 1040(w);935(s); 840(s).

EXAMPLE 522-Methyl-2-[[5-(phenylmethyl)-1,2,3-thiadiazol-4-yl]thio]propanoic acid,ethyl ester

A solution of 1.99 g of 5-(phenylmethyl)-1,2,3-thiadiazole-4-thiol,sodium salt in 30 ml of ethanol was stirred overnight with 1.96 g ofethyl 2-bromoisobutyrate and then concentrated in vacuo. The residue wastaken up in ether, filtered, and evaporated in vacuo. The oily residuewas purified as described in Example 50, giving a yellow oil. Protonnuclear magnetic resonance (δ[ppm], CDCl₃) 90MHz: 1.22 (t, 3H); 1.67 (s,2 CH₃ 's); 4.12 (q, 2H); 4.31 (s, CH₂); 7.30 (6s, SH).

EXAMPLE 53 3-[(5-Phenyl-1,2,3-thiadiazol-4-yl)thio]propanenitrile

A mixture of 22.4 g of 2-(2-phenyl-1-thioxoethyl)hydrazinecarboxylicacid, methyl ester, 10.6 g of acrylonitrile, 1.0 ml of triethylamine and100 ml of benzene was heated at reflux for 18 hours, then cooled andconcentrated in vacuo. The resulting oil was purified by chromatography,giving [Z(andE)]-[1-[(2-cyanoethyl)thio]-2-phenylethylidene]hydrazinecarboxylic acid,methyl ester.

A solution of 21 g of the above ester, 20 ml of thionyl chloride and 150ml of dichloromethane was heated at reflux for 3 hours, then cooled,poured onto chipped ice and extracted twice with ether. The extractswere combined, washed with water twice, 5% sodium bicarbonate twice,water, saturated sodium chloride, dried and concentrated in vacuo. Theresidual oil was chromatographed on silica gel, eluting withdichloromethane. The desired fractions were combined and evaporated,giving an oil which was taken up in dichloromethane and filtered througha bed of neutral alumina. Evaporation gave an oil which was crystallizedfrom methylcyclohexane, giving the desired compound as ivory crystals,mp 63.5°-64.5° C. Proton nuclear magnetic resonance (δ[ppm], CDCl₃)90MHz: 2.90 (t, 2H, J =6.5Hz, CH₂ CN); 3.55 (t, 2H, SCH₂); 7.54 (m, 5H,C₆ H₅). Infrared absorption spectrum (KBr pellet): 2250(m); 1430(s);1325(m); 1295(m); 1260(s); 1215(m); 1185(s); 935(s); 765(s); 695(s).

EXAMPLE 54 1,2,3-Thiadiazole-4-thiol, sodium salt

A mixture of 604 mg of 3-(1,2,3-thiadiazo1-4-ylthio)propionic acid,ethyl ester, 150 mg of sodium methoxide and 15 ml of methanol wasallowed to stand for 3 hours, then evaporated to 3-4 ml and 100 ml ofether was added. Chilling produced a solid which was collected, giving333 mg of the desired compound. Proton nuclear magnetic resonance(δ[ppm], CD₃ OD) 90MHz: 7.86 (s, 1H, H-5).

EXAMPLE 55 5-Methyl-1,2,3-thiadiazole-4-thiol, sodium salt

A solution of 69.7 g of3-[(5-methyl-1,2,3-thiadiazol-4-lyl)thio]propanoic acid, ethyl ester in250 ml of dry ethanol was treated with 150 ml of 2N ethanolic sodiumethoxide. After 15 minutes, the mixture was concentrated to 75 ml anddiluted with 750 ml of ether. The resulting solid was collected, washedwith ether and dried, giving the desired product as a tan solid, mp>150°C. Proton nuclear magnetic resonance (δ[ppm], CD₃ OD) 90MHz: 2.53 (s,3H, CH₃). Infrared absorption spectrum (KBr pellet): 1620(m); 1580(m);1420(s); 1375(w); 1240(s); 1200(s); 1190(m); 1125(m); 1061(s); 1000(m);895(s).

EXAMPLE 56 5-Ethyl-1,2,3-thiadiazole-4-thiol, sodium salt

A solution of 12.3 g of 3-[(5-ethyl-1,2,3-thiadiazol-4-yl)thio]propanoicacid, ethyl ester in 100 ml of dry ethanol was treated with 60 ml of0.76M ethanolic sodium ethoxide. After 30 minutes the solvent wasremoved in vacuo to a small volume and 500 ml of dry ether was added.The resulting solid was collected, washed with ether and dried, giving7.5 g of the desired product, mp>150° C. Proton nuclear magneticresonance (δ[ppm], CD₃ OD) 90MHz: 1.31 (t, 3H, J=6.8HZ, CH₃); 2.93 (q,2H, CH₂). Infrared absorption spectrum (KBr pellet): 1615(m); 1580(m);1455(m); 1415(s); 1380(m); 1240(m); 1185(s); 1135(m).

EXAMPLE 57 5-(1,1-Dimethylethyl)-1,2,3-thiadiazole-4-thiol, sodium salt

A solution of 11.5 g of3-[[5-(1,1-dimethylethyl)1,2,3-thiadiazol-4-yl]thio]propanoic acid,methyl ester in 100 ml of dry methanol was treated with 42 ml of 1Mmethanolic sodium methoxide. After standing one hour, the solvent wasremoved in vacuo to 20 ml and the suspension was diluted with dry ether.The solid was collected, washed with ether, dried, dissolved in 100 mlof methanol, filtered and concentrated to 10-15 ml. The concentrate wasdiluted with t-butyl methyl ether and the solid collected and dried,giving 5.7 g of the desired compound as yellow needles, mp>200° C.Proton nuclear magnetic resonance (δ[ppm], CD₃ OD) 90MHz: 1.55 (s, 9H,t-butyl). Infrared absorption spectrum (KBr pellet): 1605(w); 1450-1465,1365(s); 1255(m); 1158(m); 928(s).

EXAMPLE 58 5-Phenyl-1,2,3-thiadiazole-4-thiol, potassium salt

A solution of 1.8 g of 3-[(5-phenyl-1,2,3-thiadiazol-4-yl)thio]propanoicacid, ethyl ester in 20 ml of anhydrous ethanol was treated with 10 mlof 0.665M ethanolic potassium ethoxide. After 3 hours the solvent wasremoved in vacuo and the residue suspended in anhydrous ether. The solidwas collected, giving 1.3 g of the desired compound as yellow crystals.Proton nuclear resonance (δ[ppm], CD₃ OD) 90MHz: [7.40 (m, 1H); 7.45 (m,2H); 8.06 (m, 2H);(C₆ H₅)]. Infrared absorption spectrum (KBr pellet):1598(w); 1499(w); 1405(w); 1262(m); 1195(s); 1127(m); 930-940; 760(s);680-700(s).

EXAMPLE 59

5-(4-Methylphenyl)-1,2,3-thiadiazole-4-thiol, potassium salt

A suspension of 13.8 g of3-[[5-(4-methylphenyl)1,2,3-thiadiazol-4-yl]thio]propanoic acid, ethylester in 250 ml of dry ethanol was treated with 200 ml of 1M potassiumethoxide in ethanol. After 1.5 hours the solvent was evaporated in vacuoto about 100 ml and 400 ml of anhydrous ether was added. The resultingsolid was collected, washed with ether, redissolved in methanol,filtered, concentrated to a small volume and diluted with 400 ml ofanhydrous ether. The solid was collected and dried in vacuo, giving 11.5g of the desired compound, mp >12520 C. (dec.). Proton nuclear magneticresonance (δ[ppm], CD₃ OD) 90MHz: 2.35 (s, 3H, CH₃); [7.24 (d, 2H,J=8.5Hz) and 8.05 (d, 2H)(C₆ H₄)]. Infrared absorption spectrum (KBrpellet): 1605(w); 1520(m); 1400(s); 1265(m); 1195(s); 1135 (m); 930(m);835(s); 8.0(s).

EXAMPLE 60 5-[4-(1,1-Dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol,potassium salt

A solution of 15.9 g of3-[[5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazol-4-yl]thio]propanoicacid, ethyl ester in 75 ml of anhydrous ethanol was treated with 105 mlof 0.5M potassium ethoxide in ethanol. After 3 hours the solvent waspartially evaporated, 200 ml of anhydrous ether was added, the solid wascollected, washed with ether, redissolved in methanol, filtered andconcentrated to about 10-15 ml. A 250 ml portion of ether was added andthe solid collected and dried in vacuo, giving 13 g of the desiredcompound as a yellow solid. Proton nuclear magnetic resonance (δ[ppm],CD₃ OD) 90MHz: 1.35 (s, 9H, t-butyl); [7.42 (d, 2H, J=8.5Hz) and 8.12(d, 2H)(C₆ H₄)]. Infrared absorption spectrum (KBr pellet): 1605(w);1520(m) 1465(m); 1400(s); 1245-1270, 1170(s); 1130(m); 929(s); 820(s).

Example 61 5-[3-(Trifluoromethyl)phenyl]-1,2,3-thiadiazole-4-thiol,sodium salt

A solution of 11.6 g of3-[[5-[3-(trifluoromethyl)phenyl]-1,2,3-thiadiazol-4-yl]thio]propanoicacid, methyl ester in 100 ml of dry methanol was treated with 32 ml of1M methanolic sodium methoxide. After one hour the solvent was removedin vacuo, the residue was suspended in ether and the solid collected.This solid was taken up in dry methanol, filtered and concentrated to anoil. The oil was triturated with dry ether and the solid collected anddried in vacuo, giving 6.8 g of the desired compound as a yellow powder,mp >200° C. Proton nuclear magnetic resonance (67 [ppm], CD₃ OD) 90MHz:[7.55 (m, 2H); 8.20 (m, 1H) and 8.75 (m, 1H)(C₆ H₄)]. Infraredabsorption spectrum (KBr pellet): 1605(w); 1442(m); 1375(m); 1300-1320,1240(m); 1165-1180(s); 1110-1130(m); 1065(m); 1002(m); 920(s); 878(s);794(s); 687(s).

What is claimed is:
 1. A compound having the formula: ##STR15## whereinR₁ is selected from the group consisting of hydrogen; alkyl(C₁ -C₆);polyfluorinated alkyls(C₁ -C₆); phenyl; (multisubstituted)phenyl whereinthe substituents are selected from alkyl(C₁ -C₆), alkoxy(C₁ C₃), chloro,fluoro and trifluoromethyl; naphthyl; thienyl; phenylthio;tetrahydropyranyl; benzyl; and --COOC₂ H₅ ; and R₂ is selected from thegroup consisting of amino and alkoxy(C₁ -C₃).
 2. A compound as definedin claim 1 which is 2-(1-thioxoethyl)hydrazinecarboxylic acid, methylester.
 3. A compound as defined in claim 1 which is2-(1-thioxoethyl)hydrazinecarboxylic acid, ethyl ester.
 4. A compound asdefined in claim 1 which is2-(3,3-dimethyl-1-thioxobutyl)hydrazinecarboxylic acid, methyl ester. 5.A compound as defined in claim 1 which is2-(2-phenyl-1-thioxoethyl)hydrazinecarboxylic acid, methyl ester.
 6. Acompound as defined in claim 1 which is2-[2-(4-methylphenyl)-l-thioxoethyl)hydrazinecarboxylic acid, methylester.
 7. A compound as defined in claim 1 which is2-[2-(4-(1,1-dimethylethyl)phenyl[-1-thioxoethyl]hydrazinecarboxylicacid, methyl ester.
 8. A compound as defined in claim 1 which is2-[2-(4-methoxyphenyl)-1-thioxoethyl]hydrazinecarboxylic acid, methylester.
 9. A compound as defined in claim 1 which is2-[1-thioxo-2-(3,4,5-trimethoxyphenyl)ethyl]hydrazinecarboxylic acid,methyl ester.
 10. A compound as defined in claim 1 which is2-[2-(2-naphthyl)-1-thioxoethyl]hydrazinecarboxylic acid, methyl ester.11. A compound as defined in claim 1 which is2-[2-(2-thienyl)-I-thioxoethyl]hydrazinecarboxylic acid, methyl ester.12. A compound as defined in claim 1 which is2-[2-(4-chlorophenyl)-I-thioxoethyl]hydrazinecarboxylic acid, methylester.
 13. A compound as defined in claim 1 which is2-[2-(4-fluorophenyl)-1-thioxoethyl]hydrazinecarboxylic acid, methylester.
 14. A compound as defined in claim 1 which is2-[2-(3-methoxyphenyl)-1-thioxoethyl]hydrazinecarboxylic acid, methylester.
 15. A compound as defined in claim 1 which is2-[I-thioxo-2-[3-(trifluoromethyl)phenyl]ethyl]hydrazinecarboxylic acid,methyl ester.
 16. A compound as defined in claim 1 which is2-(3-ethoxy-3-oxo-1-thioxopropyl)hydrazinecarboxylic acid, methyl ester.17. A compound as defined in claim 1 which is2-[2-(phenylthio)-1-thioxoethyl]hydrazinecarboxylic acid, methyl ester.18. A compound as defined in claim 1 which is2-[2-tetrahydro-2H-pyran-2-yl)-1-thioxoethyl]hydrazinecarboxylic acid,methyl ester.
 19. A compound as defined in claim 1 which is2-(aminocarbonyl)hydrazine benzenepropanethioic acid.
 20. A compound asdefined in claim 1 which is 2-(aminocarbonyl)hydrazide propanethioicacid.
 21. A compound as defined in claim 1 which is2-(aminocarbonyl)hydrazide butanethioic acid.